Is MC2R p.Pro273Ser (c.817C>T) pathogenic?

MC2R p.Pro273Ser (c.817C>T) is classified Likely pathogenic in MC2R (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: likely pathogenic (0.9539); Absent from gnomAD v4.1.

How common is MC2R p.Pro273Ser (c.817C>T) in the general population?

MC2R p.Pro273Ser (c.817C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MC2R p.Pro273Ser (c.817C>T)?

AlphaMissense predicts likely pathogenic (score 0.9539) — an in-silico prediction, not a clinical call.

MC2R p.Pro273Ser

c.817C>T · rs1351304647 · VCV2498736

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9539 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9539	likely pathogenic ✓ concordant with ClinVar · top 5% in MC2R
REVEL	0.976	strongly pathogenic-leaning
SaProt	LLR -11.76	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 0.95	unconstrained · MANE · 890 bp · p 0.33 · regional, not allelic
Overall
CADD	27.1	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: MC2R
Protein: p.Pro273Ser
Coding: c.817C>T
MANE Select: NM_000529
dbSNP: rs1351304647
Type: single nucleotide variant
Location: chr18:13884702 (GRCh38)
Gene constraint: LOEUF 1.39 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.11 · 2 PDB
Residue 273: an α-helix

Full MC2R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MC2R p.Arg137Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
MC2R p.Arg146His Pathogenic/Likely pathogenic ★★ ⚠ same type
MC2R p.Ser256Phe Pathogenic/Likely pathogenic ★★ same type
MC2R p.Ser74Ile Pathogenic ★★ same type
MC2R c.*578C>A Uncertain significance ★★ same type
MC2R c.*971G>C Uncertain significance ★★ same type
MC2R c.*996A>T Uncertain significance ★★ same type
MC2R c.*998T>A Uncertain significance ★★ same type

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/mc2r-p-pro273ser (accessed [today's date]).

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