Is CMTM4 p.Ser15Pro (c.43T>C) pathogenic?

CMTM4 p.Ser15Pro (c.43T>C) is classified Uncertain significance in CMTM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely pathogenic (0.6519); Very rare (popmax 0.00418%, nfe).

How common is CMTM4 p.Ser15Pro (c.43T>C) in the general population?

CMTM4 p.Ser15Pro (c.43T>C) is very rare (popmax 0.00418%, nfe) (gnomAD).

What do computational predictors say about CMTM4 p.Ser15Pro (c.43T>C)?

AlphaMissense predicts likely pathogenic (score 0.6519) — an in-silico prediction, not a clinical call.

CMTM4 p.Ser15Pro

c.43T>C · VCV4004062

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6519 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00418%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6519	likely pathogenic
REVEL	0.217	benign-leaning
SaProt	LLR -6.19	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 0.72, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 92 bp · p 0.00077 · regional, not allelic
Overall
CADD	28.7	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 0.00418% European (non-Finnish) · 42/1,004,464 alleles

Filtering AF 0.00313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00278%

Overall 0.00339% 43/1,267,406 alleles · very rare exomes 43/1,117,088 · genomes 0/150,318 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00418%	23,916
Remaining individualsnot grpmax-eligible	0.00216%	46,246

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: CMTM4
Protein: p.Ser15Pro
Coding: c.43T>C
MANE Select: NM_181521
Type: single nucleotide variant
Location: chr16:66696483 (GRCh38)
Gene constraint: LOEUF 1.136 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.82
Residue 15: the 'disordered' region

Full CMTM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CMTM4 c.*4764C>A Uncertain significance ★ ⚠ same type
CMTM4 p.Ala160Val Uncertain significance ★ ⚠ same type
CMTM4 p.Ala41Val Uncertain significance ★ ⚠ same type
CMTM4 p.Arg180His Uncertain significance ★ ⚠ same type
CMTM4 p.Arg191Cys Uncertain significance ★ same type
CMTM4 p.Arg200Cys Uncertain significance ★ ⚠ same type
CMTM4 p.Arg200His Uncertain significance ★ ⚠ same type
CMTM4 p.Arg205Cys 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/cmtm4-p-ser15pro (accessed [today's date]).

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