Is MC2R p.Phe235fs (c.702del) pathogenic?

MC2R p.Phe235fs (c.702del) is classified Pathogenic in MC2R (ClinVar, Single submitter, 1 submitter; last evaluated 2015-04-20). Very rare (popmax 0.000169%, nfe); Associated with glucocorticoid deficiency 1.

What condition is associated with MC2R p.Phe235fs (c.702del)?

MC2R p.Phe235fs (c.702del) is associated with glucocorticoid deficiency 1 (ClinVar).

How common is MC2R p.Phe235fs (c.702del) in the general population?

MC2R p.Phe235fs (c.702del) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Familial glucocorticoid deficiency inherited?

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

MC2R p.Phe235fs

c.702del · rs1555619372 · VCV444063

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

glucocorticoid deficiency 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,008 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,984 alleles · very rare exomes 1/1,461,774 · genomes 1/152,210 · joint denominator

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.Phe235fs
Coding: c.702del
MANE Select: NM_000529
dbSNP: rs1555619372
Type: Deletion
Location: chr18:13884817 (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 235: 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.Arg145fs Likely pathogenic ★ same condition
MC2R p.Val187fs Pathogenic ★ same condition
MC2R p.Arg137Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
MC2R p.Arg146His Pathogenic/Likely pathogenic ★★ ⚠ same condition
MC2R p.Ile154fs Pathogenic ★★ same condition
MC2R p.Phe230fs Pathogenic/Likely pathogenic ★★ same condition
MC2R p.Ser74Ile Pathogenic ★★ same condition
MC2R c.*578C>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-phe235fs (accessed [today's date]).

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