Is MC2R p.Ser117Pro (c.349T>C) pathogenic?

MC2R p.Ser117Pro (c.349T>C) is classified Uncertain significance in MC2R (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-15). AlphaMissense: likely pathogenic (0.9487); Absent from gnomAD v4.1; Associated with glucocorticoid deficiency 1.

What condition is associated with MC2R p.Ser117Pro (c.349T>C)?

MC2R p.Ser117Pro (c.349T>C) is associated with glucocorticoid deficiency 1 (ClinVar).

How common is MC2R p.Ser117Pro (c.349T>C) in the general population?

MC2R p.Ser117Pro (c.349T>C) is absent from gnomAD v4.1 (gnomAD).

How is Familial glucocorticoid deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MC2R p.Ser117Pro (c.349T>C)?

AlphaMissense predicts likely pathogenic (score 0.9487) — an in-silico prediction, not a clinical call.

MC2R p.Ser117Pro

c.349T>C · rs2515239237 · VCV2441760

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9487 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

glucocorticoid deficiency 1

Computational evidence

Protein change
AlphaMissense	0.9487	likely pathogenic · top 5% in MC2R
REVEL	0.329	indeterminate
SaProt	LLR -14.35	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 890 bp · p 0.33 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Ser117Pro
Coding: c.349T>C
MANE Select: NM_000529
dbSNP: rs2515239237
Type: single nucleotide variant
Location: chr18:13885170 (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 117: an α-helix

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

Disease context

glucocorticoid deficiency 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial glucocorticoid deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Ireland)

Similar variants

MC2R p.Arg137Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
MC2R p.Arg146His Pathogenic/Likely pathogenic ★★ ⚠ same condition
MC2R p.Ser74Ile Pathogenic ★★ same condition
MC2R c.*578C>A Uncertain significance ★★ same condition
MC2R c.*971G>C Uncertain significance ★★ same condition
MC2R c.*996A>T Uncertain significance ★★ same condition
MC2R c.*998T>A Uncertain significance ★★ same condition
MC2R p.Ala126Val 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/mc2r-p-ser117pro (accessed [today's date]).

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