Is MC2R p.Arg145= (c.435C>T) pathogenic?

MC2R p.Arg145= (c.435C>T) is classified Conflicting classifications of pathogenicity in MC2R (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2018-02-12). Ultra-rare (popmax 0.0144%, nfe); Associated with glucocorticoid deficiency 1.

What condition is associated with MC2R p.Arg145= (c.435C>T)?

MC2R p.Arg145= (c.435C>T) is associated with glucocorticoid deficiency 1 (ClinVar).

How common is MC2R p.Arg145= (c.435C>T) in the general population?

MC2R p.Arg145= (c.435C>T) is ultra-rare (popmax 0.0144%, nfe) (gnomAD).

How is Familial glucocorticoid deficiency inherited?

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

MC2R p.Arg145=

c.435C>T · rs369830440 · VCV326196

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0144%, nfe)

Conditions

glucocorticoid deficiency 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.15	GERP -2.5, phastCons 0.001
Overall
CADD	5.959	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0144% European (non-Finnish) · 170/1,180,044 alleles

Filtering AF 0.0126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.0132% 213/1,614,156 alleles · ultra-rare exomes 191/1,461,872 · genomes 22/152,284 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0946%	1,057
Remaining individualsnot grpmax-eligible	0.0176%	5,683
European (non-Finnish)grpmax	0.0144%	6,941
Admixed American	0.00333%	30,008
African / African-American	0.00267%	37,514

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.Arg145=
Coding: c.435C>T
MANE Select: NM_000529
dbSNP: rs369830440
Type: single nucleotide variant
Location: chr18:13885084 (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.Arg145Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MC2R p.Arg145fs Likely pathogenic ★ same residue
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.Ser74Ile Pathogenic ★★ same condition
MC2R c.*578C>A Uncertain significance ★★ same condition
MC2R c.*971G>C 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-arg145 (accessed [today's date]).

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