Is MC2R p.Pro27Arg (c.80C>G) pathogenic?

MC2R p.Pro27Arg (c.80C>G) is classified Conflicting classifications of pathogenicity in MC2R (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-04-01). AlphaMissense: likely pathogenic (0.5687); Rare (popmax 0.434%, nfe); Associated with glucocorticoid deficiency 1.

What condition is associated with MC2R p.Pro27Arg (c.80C>G)?

MC2R p.Pro27Arg (c.80C>G) is associated with glucocorticoid deficiency 1 (ClinVar).

How common is MC2R p.Pro27Arg (c.80C>G) in the general population?

MC2R p.Pro27Arg (c.80C>G) is rare (popmax 0.434%, 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.Pro27Arg (c.80C>G)?

AlphaMissense predicts likely pathogenic (score 0.5687) — an in-silico prediction, not a clinical call.

MC2R p.Pro27Arg

c.80C>G · rs28926178 · VCV492864

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.5687 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.434%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

glucocorticoid deficiency 1

Computational evidence

Protein change
AlphaMissense	0.5687	likely pathogenic
REVEL	0.55	indeterminate
SaProt	LLR -9.55	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 890 bp · p 0.33 · regional, not allelic
Overall
CADD	25.6	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

Grpmax group 0.434% European (non-Finnish) · 5,121/1,179,918 alleles

Filtering AF 0.424% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.42%

Overall 0.369% 5,949/1,613,930 alleles · rare exomes 5,545/1,461,786 · genomes 404/152,144 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.1%	91
European (non-Finnish)grpmax	0.434%	230
Remaining individualsnot grpmax-eligible	0.384%	260
Admixed American	0.132%	759
Finnishnot grpmax-eligible	0.0906%	1,104
South Asian	0.0791%	1,265
African / African-American	0.0693%	1,442
Middle Eastern	0.033%	3,030

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro27Arg
Coding: c.80C>G
MANE Select: NM_000529
dbSNP: rs28926178
Type: single nucleotide variant
Location: chr18:13885439 (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 27: a UniProt-annotated variant site (in)

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-pro27arg (accessed [today's date]).

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