Is MC4R p.Val253Phe (c.757G>T) pathogenic?

MC4R p.Val253Phe (c.757G>T) is classified Uncertain significance in MC4R (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-03). AlphaMissense: ambiguous (0.4885); Absent from gnomAD v4.1; Associated with MC4R-related disorder.

What condition is associated with MC4R p.Val253Phe (c.757G>T)?

MC4R p.Val253Phe (c.757G>T) is associated with MC4R-related disorder (ClinVar).

How common is MC4R p.Val253Phe (c.757G>T) in the general population?

MC4R p.Val253Phe (c.757G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MC4R p.Val253Phe (c.757G>T)?

AlphaMissense predicts ambiguous (score 0.4885) — an in-silico prediction, not a clinical call.

MC4R p.Val253Phe

c.757G>T · VCV3344645

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4885 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

MC4R-related disorder

Computational evidence

Protein change
AlphaMissense	0.4885	ambiguous
REVEL	0.838	moderately pathogenic-leaning
SaProt	LLR -10.75	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 995 bp · p 0.82 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

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.Val253Phe
Coding: c.757G>T
MANE Select: NM_005912
Type: single nucleotide variant
Location: chr18:60371593 (GRCh38)
Gene constraint: LOEUF 1.341 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.21 · 13 PDB
Residue 253: a UniProt-annotated variant site (risk factor for obesity; partial camp response to alpha-msh); 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.Val253Ile Uncertain significance ★★ ⚠ 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.Ala135Pro Uncertain significance ★ ⚠ 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-val253phe (accessed [today's date]).

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