Is CMTM3 p.Pro22Ser (c.64C>T) pathogenic?

CMTM3 p.Pro22Ser (c.64C>T) is classified Uncertain significance in CMTM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely benign (0.0727); No allele count reported in gnomAD v4.1 (AN 1,409,294).

How common is CMTM3 p.Pro22Ser (c.64C>T) in the general population?

CMTM3 p.Pro22Ser (c.64C>T) is no allele count reported in gnomAD v4.1 (AN 1,409,294) (gnomAD).

What do computational predictors say about CMTM3 p.Pro22Ser (c.64C>T)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

CMTM3 p.Pro22Ser

c.64C>T · VCV4004059

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,409,294)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.36	GERP -2.2, phastCons 0.007
Regional constraint	o/e 0.91	unconstrained · MANE · 7,828 bp · p 0.16 · regional, not allelic
Overall
CADD	4.582	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,409,294). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CMTM3
Protein: p.Pro22Ser
Coding: c.64C>T
MANE Select: NM_181553
Type: single nucleotide variant
Location: chr16:66604869 (GRCh38)
Gene constraint: LOEUF 0.801 · pLI 0.25 (gnomAD)
Structure: AlphaFold pLDDT 79.99

Full CMTM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CMTM3 p.Pro22Leu Uncertain significance ★ ⚠ same residue
CMTM3 p.Ala29Thr Uncertain significance ★ ⚠ same type
CMTM3 p.Ala61Gly Uncertain significance ★ ⚠ same type
CMTM3 p.Ala61Pro Uncertain significance ★ same type
CMTM3 p.Ala61Val Uncertain significance ★ ⚠ same type
CMTM3 p.Arg105Cys Uncertain significance ★ ⚠ same type
CMTM3 p.Arg105Ser Uncertain significance ★ ⚠ same type
CMTM3 p.Arg28Cys 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/cmtm3-p-pro22ser (accessed [today's date]).

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