Is CMC4 p.Arg36Cys (c.106C>T) pathogenic?

CMC4 p.Arg36Cys (c.106C>T) is classified Uncertain significance in CMC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-07). AlphaMissense: likely benign (0.2319); Very rare (popmax 0.00352%, sas).

How common is CMC4 p.Arg36Cys (c.106C>T) in the general population?

CMC4 p.Arg36Cys (c.106C>T) is very rare (popmax 0.00352%, sas) (gnomAD).

What do computational predictors say about CMC4 p.Arg36Cys (c.106C>T)?

AlphaMissense predicts likely benign (score 0.2319) — an in-silico prediction, not a clinical call.

CMC4 p.Arg36Cys

c.106C>T · rs782008762 · VCV2265343

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2319 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00352%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2319	likely benign
REVEL	0.322	indeterminate
SaProt	LLR -14.08	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,177 bp · p 0.92 · regional, not allelic
Overall
CADD	27.9	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 0.00352% South Asian · 2/56,781 alleles

Filtering AF 0.000584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000219%

Overall 0.000182% 2/1,097,119 alleles · very rare

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: CMC4
Protein: p.Arg36Cys
Coding: c.106C>T
MANE Select: NM_001018024
dbSNP: rs782008762
Type: single nucleotide variant
Location: chrX:155061944 (GRCh38)
Structure: AlphaFold pLDDT 86.19 · 3 PDB
Residue 36: the chch domain; an α-helix; a disulfide bond

Full CMC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CMC4 p.Arg63Gln Uncertain significance ★ ⚠ same type
CMC4 p.Gln3Arg Uncertain significance ★ ⚠ same type
CMC4 p.Ile14Thr Uncertain significance ★ ⚠ same type
CMC4 p.Lys16Gln Uncertain significance ★ ⚠ same type
CMC4 p.Met24Thr Uncertain significance ★ ⚠ same type
CMC4 p.Pro2Leu Uncertain significance ★ ⚠ same type
CMC4 p.Ser65Pro Uncertain significance ★ ⚠ same type
MTCP1 p.Leu61Pro Uncertain significance ★ ⚠ same type

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/cmc4-p-arg36cys (accessed [today's date]).

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