Is MC1R p.Pro72= (c.216C>T) pathogenic?

MC1R p.Pro72= (c.216C>T) is classified Likely benign in MC1R (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-18). Very rare (popmax 0.00167%, amr).

How common is MC1R p.Pro72= (c.216C>T) in the general population?

MC1R p.Pro72= (c.216C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

MC1R p.Pro72=

c.216C>T · VCV4052418

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.79	GERP -3.1, phastCons 1
Overall
CADD	9.606	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,026 alleles

Overall 0.000124% 2/1,613,338 alleles · very rare exomes 2/1,460,984 · genomes 0/152,354 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,026
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Pro72=
Coding: c.216C>T
MANE Select: NM_002386
Type: single nucleotide variant
Location: chr16:89919474 (GRCh38)
Gene constraint: LOEUF 1.933 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.62 · 5 PDB
Residue 72: an α-helix

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

Similar variants

MC1R p.Pro72Arg Uncertain significance ★★ same residue
MC1R p.Pro72Thr Uncertain significance ★ ⚠ same residue
MC1R c.-110A>C Uncertain significance ★★ same type
MC1R c.-504G>A Uncertain significance ★★ same type
MC1R c.*739A>T Uncertain significance ★★ same type
MC1R p.Ala105Thr Uncertain significance ★★ ⚠ same type
MC1R p.Ala137Ser Uncertain significance ★★ ⚠ same type
MC1R p.Ala149Thr 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/mc1r-p-pro72 (accessed [today's date]).

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