Is MC1R p.Pro22= (c.66C>T) pathogenic?

MC1R p.Pro22= (c.66C>T) is classified Conflicting classifications of pathogenicity in MC1R (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-22). Rare (popmax 0.198%, eas); Associated with melanoma, cutaneous malignant, susceptibility to, 5.

What condition is associated with MC1R p.Pro22= (c.66C>T)?

MC1R p.Pro22= (c.66C>T) is associated with melanoma, cutaneous malignant, susceptibility to, 5 (ClinVar).

How common is MC1R p.Pro22= (c.66C>T) in the general population?

MC1R p.Pro22= (c.66C>T) is rare (popmax 0.198%, eas) (gnomAD).

MC1R p.Pro22=

c.66C>T · rs773395822 · VCV884727

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.198%, eas)

Conditions

melanoma, cutaneous malignant, susceptibility to, 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.7	GERP -4.2
Overall
CADD	0.875	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.198% East Asian · 89/44,852 alleles

Filtering AF 0.165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.153%

Overall 0.00558% 90/1,612,054 alleles · rare exomes 87/1,459,872 · genomes 3/152,182 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.198%	504
European (non-Finnish)	8.48e-05%	1,179,444

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: MC1R
Protein: p.Pro22=
Coding: c.66C>T
MANE Select: NM_002386
dbSNP: rs773395822
Type: single nucleotide variant
Location: chr16:89919324 (GRCh38)
Gene constraint: LOEUF 1.933 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.62 · 5 PDB

Full MC1R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

melanoma, cutaneous malignant, susceptibility to, 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MC1R c.-110A>C Uncertain significance ★★ same condition
MC1R c.-504G>A Uncertain significance ★★ same condition
MC1R c.*739A>T Uncertain significance ★★ same condition
MC1R p.Ala105Thr Uncertain significance ★★ ⚠ same condition
MC1R p.Ala137Ser Uncertain significance ★★ ⚠ same condition
MC1R p.Ala149Thr Uncertain significance ★★ ⚠ same condition
MC1R p.Ala171Gly Uncertain significance ★★ ⚠ same condition
MC1R p.Ala181Gly 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/mc1r-p-pro22 (accessed [today's date]).

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