Is MC2R p.Val45Ile (c.133G>A) pathogenic?

MC2R p.Val45Ile (c.133G>A) is classified Uncertain significance in MC2R (ClinVar, Multiple submitters, 3 submitters; last evaluated 2020-11-05). AlphaMissense: likely benign (0.1147); Rare (popmax 0.167%, nfe); Associated with glucocorticoid deficiency 1.

What condition is associated with MC2R p.Val45Ile (c.133G>A)?

MC2R p.Val45Ile (c.133G>A) is associated with glucocorticoid deficiency 1 (ClinVar).

How common is MC2R p.Val45Ile (c.133G>A) in the general population?

MC2R p.Val45Ile (c.133G>A) is rare (popmax 0.167%, nfe) (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.Val45Ile (c.133G>A)?

AlphaMissense predicts likely benign (score 0.1147) — an in-silico prediction, not a clinical call.

MC2R p.Val45Ile

c.133G>A · rs148298654 · VCV889352

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1147 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.167%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

glucocorticoid deficiency 1

Computational evidence

Protein change
AlphaMissense	0.1147	likely benign
REVEL	0.329	indeterminate
SaProt	LLR -8.26	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.82, phastCons 0.81
Regional constraint	o/e 0.95	unconstrained · MANE · 890 bp · p 0.33 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.167% European (non-Finnish) · 1,975/1,179,984 alleles

Filtering AF 0.161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.159%

Overall 0.139% 2,236/1,614,074 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.167%	597
Remaining individualsnot grpmax-eligible	0.118%	845
Middle Eastern	0.116%	866
Admixed American	0.0883%	1,132
African / African-American	0.0853%	1,172
South Asian	0.0626%	1,598
Finnishnot grpmax-eligible	0.00937%	10,671

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: MC2R
Protein: p.Val45Ile
Coding: c.133G>A
MANE Select: NM_000529
dbSNP: rs148298654
Type: single nucleotide variant
Location: chr18:13885386 (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 45: a disulfide bond; 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

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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-val45ile (accessed [today's date]).

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