Is MC4R p.Ala135Pro (c.403G>C) pathogenic?

MC4R p.Ala135Pro (c.403G>C) is classified Uncertain significance in MC4R (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-05). AlphaMissense: likely pathogenic (0.9818); Absent from gnomAD v4.1; Associated with MC4R-related disorder.

What condition is associated with MC4R p.Ala135Pro (c.403G>C)?

MC4R p.Ala135Pro (c.403G>C) is associated with MC4R-related disorder (ClinVar).

How common is MC4R p.Ala135Pro (c.403G>C) in the general population?

MC4R p.Ala135Pro (c.403G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MC4R p.Ala135Pro (c.403G>C)?

AlphaMissense predicts likely pathogenic (score 0.9818) — an in-silico prediction, not a clinical call.

MC4R p.Ala135Pro

c.403G>C · rs2511560507 · VCV2629264

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9818 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

MC4R-related disorder

Computational evidence

Protein change
AlphaMissense	0.9818	likely pathogenic · top 8% in MC4R
REVEL	0.497	indeterminate
SaProt	LLR -13.40	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 995 bp · p 0.82 · regional, not allelic
Overall
CADD	28.3	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.Ala135Pro
Coding: c.403G>C
MANE Select: NM_005912
dbSNP: rs2511560507
Type: single nucleotide variant
Location: chr18:60371947 (GRCh38)
Gene constraint: LOEUF 1.341 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.21 · 13 PDB
Residue 135: an α-helix; a UniProt-annotated variant site (risk factor for obesity)

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

Disease context

MC4R-related disorder

Similar variants

MC4R p.Ala135Val Uncertain significance ⚠ same residue
MC4R p.Ala135= Conflicting classifications of pathogenicity ★ same residue
MC4R p.Cys271Tyr Pathogenic ★★ same condition
MC4R p.Leu300Pro Uncertain significance ★★ ⚠ same condition
MC4R p.Leu328Ter Uncertain significance ★★ same condition
MC4R p.Ser99Ter Likely pathogenic ★ same condition
MC4R p.Pro299His Conflicting classifications of pathogenicity ★ ⚠ same condition
MC4R p.Ser139Arg Likely pathogenic 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-ala135pro (accessed [today's date]).

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