Is MC2R p.Arg137Pro (c.410G>C) pathogenic?

MC2R p.Arg137Pro (c.410G>C) is classified Pathogenic in MC2R (ClinVar, No assertion criteria, 1 submitter; last evaluated 2009-01-23). AlphaMissense: likely pathogenic (0.8652); Absent from gnomAD v4.1; Associated with Glucocorticoid Deficiency.

What condition is associated with MC2R p.Arg137Pro (c.410G>C)?

MC2R p.Arg137Pro (c.410G>C) is associated with Glucocorticoid Deficiency (ClinVar).

How common is MC2R p.Arg137Pro (c.410G>C) in the general population?

MC2R p.Arg137Pro (c.410G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MC2R p.Arg137Pro (c.410G>C)?

AlphaMissense predicts likely pathogenic (score 0.8652) — an in-silico prediction, not a clinical call.

MC2R p.Arg137Pro

c.410G>C · rs1208417750 · VCV492865

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8652 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Glucocorticoid Deficiency

Computational evidence

Protein change
AlphaMissense	0.8652	likely pathogenic ✓ concordant with ClinVar
REVEL	0.273	benign-leaning
SaProt	LLR -15.69	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.9	GERP -0.43, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 890 bp · p 0.33 · regional, not allelic
Overall
CADD	23.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MC2R
Protein: p.Arg137Pro
Coding: c.410G>C
MANE Select: NM_000529
dbSNP: rs1208417750
Type: single nucleotide variant
Location: chr18:13885109 (GRCh38)
Gene constraint: LOEUF 1.39 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.11 · 2 PDB
Residue 137: a UniProt-annotated variant site (found in a glucocorticoid deficiency patient carrying also mutation i-74); a UniProt-annotated variant site (in gccd1; partial loss of activity); a turn

Full MC2R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Glucocorticoid Deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MC2R p.Arg137Trp Pathogenic/Likely pathogenic ★★ ⚠ same residue
MC2R p.Arg137Gln Uncertain significance ★★ ⚠ same residue
MC2R p.Arg137= Uncertain significance ★ same residue
MC2R p.Cys191Ter Pathogenic same condition
MC2R p.Trp155Cys Likely pathogenic same condition
MC2R p.Arg146His Pathogenic/Likely pathogenic ★★ ⚠ same type
MC2R p.Ser256Phe Pathogenic/Likely pathogenic ★★ same type
MC2R p.Ser74Ile Pathogenic ★★ 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/mc2r-p-arg137pro (accessed [today's date]).

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