Is CMTM4 p.Thr192Lys (c.575C>A) pathogenic?

CMTM4 p.Thr192Lys (c.575C>A) is classified Uncertain significance in CMTM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: ambiguous (0.5592); Very rare (popmax 0.00281%, nfe).

How common is CMTM4 p.Thr192Lys (c.575C>A) in the general population?

CMTM4 p.Thr192Lys (c.575C>A) is very rare (popmax 0.00281%, nfe) (gnomAD).

What do computational predictors say about CMTM4 p.Thr192Lys (c.575C>A)?

AlphaMissense predicts ambiguous (score 0.5592) — an in-silico prediction, not a clinical call.

CMTM4 p.Thr192Lys

c.575C>A · VCV4654743

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5592 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00281%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5592	ambiguous
REVEL	0.223	benign-leaning
SaProt	LLR -7.99	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 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 74 kb · p 0.077 · regional, not allelic
Overall
CADD	25.4	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 0.00281% European (non-Finnish) · 33/1,173,284 alleles

Filtering AF 0.00201% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00219% 35/1,600,836 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00281%	35,554
African / African-American	0.00267%	37,399

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.Thr192Lys
Coding: c.575C>A
MANE Select: NM_181521
Type: single nucleotide variant
Location: chr16:66622110 (GRCh38)
Gene constraint: LOEUF 1.136 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.82

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-thr192lys (accessed [today's date]).

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