Is CMC4 p.Cys50Ser (c.149G>C) pathogenic?

CMC4 p.Cys50Ser (c.149G>C) is classified Likely benign in CMC4 (ClinVar, No assertion criteria, 3 submitters). AlphaMissense: likely pathogenic (0.9728); Ultra-rare (popmax 0.087%, nfe).

How common is CMC4 p.Cys50Ser (c.149G>C) in the general population?

CMC4 p.Cys50Ser (c.149G>C) is ultra-rare (popmax 0.087%, nfe) (gnomAD).

What do computational predictors say about CMC4 p.Cys50Ser (c.149G>C)?

AlphaMissense predicts likely pathogenic (score 0.9728) — an in-silico prediction, not a clinical call.

CMC4 p.Cys50Ser

c.149G>C · rs146554247 · VCV1205949

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9728 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.087%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9728	likely pathogenic · top 2% in CMC4
REVEL	0.837	moderately pathogenic-leaning
SaProt	LLR -14.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,177 bp · p 0.92 · regional, not allelic
Overall
CADD	23.4	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 0.087% European (non-Finnish) · 779/895,155 alleles

Filtering AF 0.082% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0798%

Overall 0.0658% 796/1,210,114 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.087%	1,149
Remaining individualsnot grpmax-eligible	0.0294%	3,401
African / African-American	0.00349%	28,662
Finnishnot grpmax-eligible	0.00215%	46,611

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.Cys50Ser
Coding: c.149G>C
MANE Select: NM_001018024
dbSNP: rs146554247
Type: single nucleotide variant
Location: chrX:155061901 (GRCh38)
Structure: AlphaFold pLDDT 86.19 · 3 PDB
Residue 50: an α-helix; a disulfide bond

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

Similar variants

CMC4 p.Arg36Cys Uncertain significance ★ ⚠ same type
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

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-cys50ser (accessed [today's date]).

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