Is MC4R p.Pro299Ser (c.895C>T) pathogenic?

MC4R p.Pro299Ser (c.895C>T) is classified Uncertain significance in MC4R (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-05). AlphaMissense: likely pathogenic (0.9942); Absent from gnomAD v4.1; Associated with BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20.

What condition is associated with MC4R p.Pro299Ser (c.895C>T)?

MC4R p.Pro299Ser (c.895C>T) is associated with BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 (ClinVar).

How common is MC4R p.Pro299Ser (c.895C>T) in the general population?

MC4R p.Pro299Ser (c.895C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MC4R p.Pro299Ser (c.895C>T)?

AlphaMissense predicts likely pathogenic (score 0.9942) — an in-silico prediction, not a clinical call.

MC4R p.Pro299Ser

c.895C>T · rs2511559991 · VCV1803912

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9942 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Computational evidence

Protein change
AlphaMissense	0.9942	likely pathogenic · top 2% in MC4R
REVEL	0.965	strongly pathogenic-leaning
SaProt	LLR -13.48	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 995 bp · p 0.82 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MC4R
Protein: p.Pro299Ser
Coding: c.895C>T
MANE Select: NM_005912
dbSNP: rs2511559991
Type: single nucleotide variant
Location: chr18:60371455 (GRCh38)
Gene constraint: LOEUF 1.341 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.21 · 13 PDB
Residue 299: a UniProt-annotated variant site (risk factor for obesity); an α-helix

Full MC4R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MC4R p.Pro299His Conflicting classifications of pathogenicity ★ ⚠ same residue
MC4R p.Asp90Asn Pathogenic ★★ same condition
MC4R p.Cys271Arg Pathogenic/Likely pathogenic ★★ same condition
MC4R p.Gly181Asp Pathogenic/Likely pathogenic ★★ same condition
MC4R p.Ile316Ser Pathogenic/Likely pathogenic ★★ same condition
MC4R c.-121G>A Uncertain significance ★★ same condition
MC4R c.-59G>A Uncertain significance ★★ same condition
MC4R p.Arg18Leu Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mc4r-p-pro299ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown