Is MC2R p.Ile265= (c.795C>T) pathogenic?

MC2R p.Ile265= (c.795C>T) is classified Conflicting classifications of pathogenicity in MC2R (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2018-08-18). Rare (popmax 0.144%, afr); Associated with glucocorticoid deficiency 1.

What condition is associated with MC2R p.Ile265= (c.795C>T)?

MC2R p.Ile265= (c.795C>T) is associated with glucocorticoid deficiency 1 (ClinVar).

How common is MC2R p.Ile265= (c.795C>T) in the general population?

MC2R p.Ile265= (c.795C>T) is rare (popmax 0.144%, afr) (gnomAD).

How is Familial glucocorticoid deficiency inherited?

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

MC2R p.Ile265=

c.795C>T · rs141349908 · VCV326192

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.144%, afr)

Conditions

glucocorticoid deficiency 1

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 1.2	GERP -0.69, phastCons 1
Overall
CADD	7.74	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.144% African / African-American · 108/75,034 alleles

Filtering AF 0.122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.114%

Overall 0.00731% 118/1,614,138 alleles · rare exomes 60/1,461,860 · genomes 58/152,278 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.144%	695
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0096%	10,418
Admixed American	0.00167%	60,030
South Asian	0.0011%	91,072
European (non-Finnish)	8.47e-05%	1,180,022

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.Ile265=
Coding: c.795C>T
MANE Select: NM_000529
dbSNP: rs141349908
Type: single nucleotide variant
Location: chr18:13884724 (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 265: 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-ile265 (accessed [today's date]).

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