Is MC3R p.Phe197= (c.591C>T) pathogenic?

MC3R p.Phe197= (c.591C>T) is classified Likely benign in MC3R (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-29). Very rare (popmax 0.00178%, nfe).

How common is MC3R p.Phe197= (c.591C>T) in the general population?

MC3R p.Phe197= (c.591C>T) is very rare (popmax 0.00178%, nfe) (gnomAD).

MC3R p.Phe197=

c.591C>T · VCV4945415

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

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 -2.1	GERP -4.9
Overall
CADD	7.944	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00178% European (non-Finnish) · 21/1,180,008 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.0013% 21/1,614,108 alleles · very rare exomes 21/1,461,852 · genomes 0/152,256 · 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: MC3R
Protein: p.Phe197=
Coding: c.591C>T
MANE Select: NM_019888
Type: single nucleotide variant
Location: chr20:56249434 (GRCh38)
Gene constraint: LOEUF 1.196 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.32 · 6 PDB
Residue 197: an α-helix

Full MC3R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MC3R p.Leu106Val Uncertain significance ★★ ⚠ same type
MC3R p.Thr13Ala Uncertain significance ★★ ⚠ same type
MC3R p.Thr157Asn Uncertain significance ★★ ⚠ same type
MC3R p.Ile189= Likely benign ★★ same type
MC3R p.Leu58= Likely benign ★★ same type
MC3R p.Val44Ile Benign ★★ same type
MC3R p.Ala139Thr Uncertain significance ★ ⚠ same type
MC3R p.Ala149Val 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/mc3r-p-phe197 (accessed [today's date]).

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