Is MC4R p.Pro230= (c.690C>T) pathogenic?

MC4R p.Pro230= (c.690C>T) is classified Likely benign in MC4R (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-06-22). Very rare (popmax 0.00666%, afr); Associated with MC4R-related disorder.

What condition is associated with MC4R p.Pro230= (c.690C>T)?

MC4R p.Pro230= (c.690C>T) is associated with MC4R-related disorder (ClinVar).

How common is MC4R p.Pro230= (c.690C>T) in the general population?

MC4R p.Pro230= (c.690C>T) is very rare (popmax 0.00666%, afr) (gnomAD).

MC4R p.Pro230=

c.690C>T · rs148026669 · VCV3032245

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00666%, afr)

Conditions

MC4R-related disorder

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 -20	GERP -5.6
Overall
CADD	0.175	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00666% African / African-American · 5/75,036 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000991% 16/1,614,142 alleles · very rare exomes 13/1,461,848 · genomes 3/152,294 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00666%	15,007
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000847%	118,001

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.Pro230=
Coding: c.690C>T
MANE Select: NM_005912
dbSNP: rs148026669
Type: single nucleotide variant
Location: chr18:60371660 (GRCh38)
Gene constraint: LOEUF 1.341 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.21 · 13 PDB
Residue 230: a UniProt-annotated variant site (risk factor for obesity; decreased localization to primary cilia); a UniProt-annotated variant site (risk factor for obesity)

Full MC4R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MC4R-related disorder

Similar variants

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
MC4R p.Ala135Val 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/mc4r-p-pro230 (accessed [today's date]).

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