Is CMTM5 p.Phe52Ser (c.155T>C) pathogenic?

CMTM5 p.Phe52Ser (c.155T>C) is classified Uncertain significance in CMTM5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely pathogenic (0.9922); Ultra-rare (popmax 0.0201%, eas).

How common is CMTM5 p.Phe52Ser (c.155T>C) in the general population?

CMTM5 p.Phe52Ser (c.155T>C) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about CMTM5 p.Phe52Ser (c.155T>C)?

AlphaMissense predicts likely pathogenic (score 0.9922) — an in-silico prediction, not a clinical call.

CMTM5 p.Phe52Ser

c.155T>C · rs771706860 · VCV3146266

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9922 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9922	likely pathogenic · top 1% in CMTM5
REVEL	0.416	indeterminate
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,232 bp · p 0.89 · regional, not allelic
Overall
CADD	27.7	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 0.0201% East Asian · 9/44,870 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.000682% 11/1,614,086 alleles · ultra-rare exomes 11/1,461,854 · genomes 0/152,232 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,986
Middle Eastern	0.0165%	6,060
European (non-Finnish)	8.47e-05%	1,179,990

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: CMTM5
Protein: p.Phe52Ser
Coding: c.155T>C
MANE Select: NM_001288746
dbSNP: rs771706860
Type: single nucleotide variant
Location: chr14:23378377 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.83
Residue 52: the marvel domain

Full CMTM5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CMTM5 p.Ala43= Benign ★★ same type
CMTM5 p.Leu74= Benign ★★ same type
CMTM5 p.Ala217Thr Uncertain significance ★ ⚠ same type
CMTM5 p.Ala24Thr Uncertain significance ★ ⚠ same type
CMTM5 p.Ala43Ser Uncertain significance ★ ⚠ same type
CMTM5 p.Ala62Thr Uncertain significance ★ ⚠ same type
CMTM5 p.Ala62Val Uncertain significance ★ ⚠ same type
CMTM5 p.Ala63Val 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/cmtm5-p-phe52ser (accessed [today's date]).

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