Is MC4R p.Tyr287Cys (c.860A>G) pathogenic?

MC4R p.Tyr287Cys (c.860A>G) is classified Uncertain significance in MC4R (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-05-12). AlphaMissense: likely pathogenic (0.6757); Very rare (popmax 0.0011%, sas); Associated with MC4R-related disorder.

What condition is associated with MC4R p.Tyr287Cys (c.860A>G)?

MC4R p.Tyr287Cys (c.860A>G) is associated with MC4R-related disorder (ClinVar).

How common is MC4R p.Tyr287Cys (c.860A>G) in the general population?

MC4R p.Tyr287Cys (c.860A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about MC4R p.Tyr287Cys (c.860A>G)?

AlphaMissense predicts likely pathogenic (score 0.6757) — an in-silico prediction, not a clinical call.

MC4R p.Tyr287Cys

c.860A>G · VCV3350114

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6757 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MC4R-related disorder

Computational evidence

Protein change
AlphaMissense	0.6757	likely pathogenic
REVEL	0.766	pathogenic-leaning
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 995 bp · p 0.82 · regional, not allelic
Overall
CADD	28.0	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

Grpmax group 0.0011% South Asian · 1/91,084 alleles

Overall 6.2e-05% 1/1,614,190 alleles · very rare exomes 1/1,461,884 · genomes 0/152,306 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MC4R
Protein: p.Tyr287Cys
Coding: c.860A>G
MANE Select: NM_005912
Type: single nucleotide variant
Location: chr18:60371490 (GRCh38)
Gene constraint: LOEUF 1.341 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.21 · 13 PDB
Residue 287: 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

MC4R-related disorder

Similar variants

MC4R p.Tyr287Ter Pathogenic ★ 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-tyr287cys (accessed [today's date]).

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