Is MC2R p.Ser7= (c.21G>A) pathogenic?

MC2R p.Ser7= (c.21G>A) is classified Uncertain significance in MC2R (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Ultra-rare (popmax 0.0379%, eas); Associated with glucocorticoid deficiency 1.

What condition is associated with MC2R p.Ser7= (c.21G>A)?

MC2R p.Ser7= (c.21G>A) is associated with glucocorticoid deficiency 1 (ClinVar).

How common is MC2R p.Ser7= (c.21G>A) in the general population?

MC2R p.Ser7= (c.21G>A) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

How is Familial glucocorticoid deficiency inherited?

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

MC2R p.Ser7=

c.21G>A · rs371151390 · VCV890041

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

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 -8.8	GERP -2.9
Overall
CADD	0.533	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0379% East Asian · 17/44,872 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00657% 106/1,614,098 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0379%	2,640
African / African-American	0.028%	3,572
Remaining individualsnot grpmax-eligible	0.0096%	10,418
Admixed American	0.00833%	12,002
European (non-Finnish)	0.00458%	21,852
South Asian	0.0022%	45,540
Finnishnot grpmax-eligible	0.00156%	64,016

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.Ser7=
Coding: c.21G>A
MANE Select: NM_000529
dbSNP: rs371151390
Type: single nucleotide variant
Location: chr18:13885498 (GRCh38)
Gene constraint: LOEUF 1.39 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.11 · 2 PDB

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.Ser7Leu Likely benign ★ same residue
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

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-ser7 (accessed [today's date]).

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