Is MC2R p.Arg145fs (c.434_440del) pathogenic?

MC2R p.Arg145fs (c.434440del) is classified Likely pathogenic in MC2R (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). Associated with glucocorticoid deficiency 1.

What condition is associated with MC2R p.Arg145fs (c.434_440del)?

MC2R p.Arg145fs (c.434_440del) is associated with glucocorticoid deficiency 1 (ClinVar).

How is Familial glucocorticoid deficiency inherited?

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

MC2R p.Arg145fs

c.434_440del · VCV3775355

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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 -0.35	GERP -3.8

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

Variant & gene context

Gene: MC2R
Protein: p.Arg145fs
Coding: c.434_440del
MANE Select: NM_000529
Type: Deletion
Location: chr18:13885079 (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 145: a disulfide bond

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.Arg145= Conflicting classifications of pathogenicity ★ same residue
MC2R p.Arg145Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MC2R p.Phe235fs Pathogenic ★ same condition
MC2R p.Val187fs Pathogenic ★ same condition
MC2R p.Arg145Gly Uncertain significance ★ ⚠ same residue
MC2R p.Arg137Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
MC2R p.Arg146His Pathogenic/Likely pathogenic ★★ ⚠ same condition
MC2R p.Ile154fs Pathogenic ★★ 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-arg145fs (accessed [today's date]).

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