UniProtKB/Swiss-Prot P32245: Variant p.Ile125Lys

Melanocortin receptor 4
Gene: MC4R
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Variant information Variant position:

125 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant:

US The variants are classified into three categories: LP/P, LB/B and US.

LP/P: likely pathogenic or pathogenic.
LB/B: likely benign or benign.
US: uncertain significance

Residue change:

From Isoleucine (I) to Lysine (K) at position 125 (I125K, p.Ile125Lys). Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.
Physico-chemical properties:

Change from medium size and hydrophobic (I) to large size and basic (K) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score:

-3 The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:

Lowest score: -4 (low probability of substitution).
Highest score: 11 (high probability of substitution).

More information can be found on the following page
Variant description:

Risk factor for OBESITY; loss of generation of cAMP in response to ligand; impaired cell surface expression. Any additional useful information about the variant.

Sequence information Variant position:

125 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length:

332 The length of the canonical sequence.
Location on the sequence:

TLLNSTDTDAQSFTVNIDNV I DSVICSSLLASICSLLSIAV The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.
Residue conservation:

The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         TLLNSTD-TDAQSFTVNIDNVIDSVICSSLLASICSLLSIAV

Mouse                         TLLNSTD-TDAQSFTVNIDNVIDSVICSSLLASICSLLSIA

Rat                           TLLNSTD-TDAQSFTVNIDNVIDSVICSSLLASICSLLSIA

Pig                           TLLNSTD-TDAQSFTVNIDNVIDSVICSSLLASICSLLSIA

Bovine                        TLLNSTD-TDAQSFTVDIDNVIDSVICSSLLASICSLLSIA

Zebrafish                     ALITGGNLTNRESIIKNMDNVFDSMICSSLLASIWSLLAIA

Sequence annotation in neighborhood:

The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:

Type: the type of sequence feature.
Positions: endpoints of the sequence feature.
Description: contains additional information about the feature.

Type	Positions	Description
Chain	1 – 332	Melanocortin receptor 4
Transmembrane	119 – 145	Helical; Name=3
Binding site	122 – 122
Binding site	126 – 126
Disulfide bond	40 – 279
Mutagenesis	122 – 122	D -> A. Loss of high-affinity ligand binding.
Mutagenesis	122 – 122	D -> N. About 50% loss of alpha-MSH signaling.
Mutagenesis	126 – 126	D -> Y. Complete abolishment of receptor function.
Helix	118 – 152

Literature citations
Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms.
Yeo G.S.H.; Lank E.J.; Farooqi I.S.; Keogh J.; Challis B.G.; O'Rahilly S.;
Hum. Mol. Genet. 12:561-574(2003)
Cited for: INVOLVEMENT IN OBESITY; VARIANTS SER-62; ASP-97; PRO-106; LYS-125; GLN-165; THR-175; ILE-253; TYR-271 AND SER-316; CHARACTERIZATION OF VARIANTS SER-62; ASP-97; PRO-106; LYS-125; GLN-165; THR-175; ILE-253; TYR-271 AND SER-316; FUNCTION;
Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.
Farooqi I.S.; Keogh J.M.; Yeo G.S.H.; Lank E.J.; Cheetham T.; O'Rahilly S.;
N. Engl. J. Med. 348:1085-1095(2003)
Cited for: INVOLVEMENT IN OBESITY; VARIANTS ALA-11; SER-62; ASP-97; ILE-103; MET-112; LYS-125; GLN-165; THR-175; LEU-251; TYR-271; ARG-271 AND SER-316; CHARACTERIZATION OF VARIANTS ALA-11; SER-62; ASP-97; ILE-103; MET-112; LYS-125; GLN-165; THR-175; LEU-251; TYR-271 AND SER-316; FUNCTION;
Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk.
Zorn S.; Bounds R.; Williamson A.; Lawler K.; Hanssen R.; Keogh J.; Henning E.; Smith M.; Fielding B.A.; Umpleby A.M.; Yasmeen S.; Marti-Solano M.; Langenberg C.; Wabitsch M.; Collet T.H.; Farooqi I.S.;
Nat. Med. 0:0-0(2025)
Cited for: INVOLVEMENT IN OBESITY; PROTECTION FROM CARDIOVASCULAR DISEASE; VARIANTS ALA-11; GLY-19; 21-TYR--TYR-332 DEL; PHE-30; ALA-34; 35-TYR--TYR-332 DEL; VAL-37; LYS-42; ILE-53; PRO-54; ASP-55; VAL-55; GLY-61; LYS-61; SER-62; VAL-68; ARG-69; THR-69; ASP-70; SER-72; ARG-76; LEU-77; 80-TYR--TYR-332 DEL; CYS-80; 84-CYS--TYR-332 DEL; 88-VAL--LEU-92 DEL; LYS-91; PRO-92; ALA-95; ILE-95; ASP-97; ASN-102; PRO-106; MET-112; TYR-122; LYS-125; GLU-126; LEU-127; ARG-131; PHE-136; PRO-136; THR-137; ARG-139; HIS-141; ASN-143; SER-144; GLY-146; ILE-150; PRO-156; MET-160; THR-161; ILE-162; GLN-165; TRP-165; ILE-166; ILE-170 DEL; VAL-170; 174-TRP--TYR-332 DEL; THR-175; PHE-177; PRO-180; THR-191; MET-200 DEL; VAL-200; LEU-202; ARG-204; PRO-211; ARG-215; THR-227; SER-232; CYS-236; ASP-238; SER-240; ASN-246; GLN-250; SER-252; ILE-253; 258-TRP--TYR-332 DEL; GLN-260; THR-260; PRO-263; ASN-269; ARG-271; TYR-271; LEU-272; PRO-273; SER-274; 276-TYR--TYR-332 DEL; LEU-284; 287-TYR--TYR-332 DEL; 295-SER--TYR-332 DEL; HIS-299; LEU-299; PRO-300; VAL-301; THR-303; TRP-305; ASN-306; 307-GLN--TYR-332 DEL; LYS-308; GLU-314; SER-316 AND LYS-331;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.