Is CMTM2 p.Phe125Ser (c.374T>C) pathogenic?

CMTM2 p.Phe125Ser (c.374T>C) is classified Uncertain significance in CMTM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: ambiguous (0.4486); Very rare (popmax 0.00822%, nfe).

How common is CMTM2 p.Phe125Ser (c.374T>C) in the general population?

CMTM2 p.Phe125Ser (c.374T>C) is very rare (popmax 0.00822%, nfe) (gnomAD).

What do computational predictors say about CMTM2 p.Phe125Ser (c.374T>C)?

AlphaMissense predicts ambiguous (score 0.4486) — an in-silico prediction, not a clinical call.

CMTM2 p.Phe125Ser

c.374T>C · VCV4654736

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4486 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00822%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4486	ambiguous
REVEL	0.092	moderately benign-leaning
SaProt	LLR -8.27	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.91, phastCons 0.017
Regional constraint	o/e 0.89	unconstrained · MANE · 8,508 bp · p 0.043 · regional, not allelic
Overall
CADD	19.43	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 0.00822% European (non-Finnish) · 97/1,180,040 alleles

Filtering AF 0.00689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00607% 98/1,614,092 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00822%	12,165
African / African-American	0.00133%	74,936

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: CMTM2
Protein: p.Phe125Ser
Coding: c.374T>C
MANE Select: NM_144673
Type: single nucleotide variant
Location: chr16:66580114 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.74
Residue 125: the marvel domain

Full CMTM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CMTM2 p.Ala181Ser Uncertain significance ★ ⚠ same type
CMTM2 p.Ala181Val Uncertain significance ★ ⚠ same type
CMTM2 p.Ala88Thr Uncertain significance ★ ⚠ same type
CMTM2 p.Ala9Thr Uncertain significance ★ ⚠ same type
CMTM2 p.Arg171Gln Uncertain significance ★ ⚠ same type
CMTM2 p.Arg171Trp Uncertain significance ★ ⚠ same type
CMTM2 p.Arg69Pro Uncertain significance ★ ⚠ same type
CMTM2 p.Arg70Cys 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/cmtm2-p-phe125ser (accessed [today's date]).

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