Is CMC4 p.Ser65Pro (c.193T>C) pathogenic?

CMC4 p.Ser65Pro (c.193T>C) is classified Uncertain significance in CMC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-27). AlphaMissense: likely benign (0.0566); Very rare (popmax 0.000224%, nfe).

How common is CMC4 p.Ser65Pro (c.193T>C) in the general population?

CMC4 p.Ser65Pro (c.193T>C) is very rare (popmax 0.000224%, nfe) (gnomAD).

What do computational predictors say about CMC4 p.Ser65Pro (c.193T>C)?

AlphaMissense predicts likely benign (score 0.0566) — an in-silico prediction, not a clinical call.

CMC4 p.Ser65Pro

c.193T>C · rs1326751704 · VCV2297735

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0566 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000224%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0566	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -11.11	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.012	GERP -0.9, phastCons 0.003
Regional constraint	o/e 1.01	unconstrained · MANE · 2,177 bp · p 0.92 · regional, not allelic
Overall
CADD	9.738	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 0.000224% European (non-Finnish) · 2/893,556 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000166% 2/1,206,573 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.Ser65Pro
Coding: c.193T>C
MANE Select: NM_001018024
dbSNP: rs1326751704
Type: single nucleotide variant
Location: chrX:155061857 (GRCh38)
Structure: AlphaFold pLDDT 86.19 · 3 PDB

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
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-ser65pro (accessed [today's date]).

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