Is CMTM4 p.Phe169Tyr (c.506T>A) pathogenic?

CMTM4 p.Phe169Tyr (c.506T>A) is classified Uncertain significance in CMTM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-31). AlphaMissense: likely benign (0.1401); Very rare (popmax 0.00153%, nfe).

How common is CMTM4 p.Phe169Tyr (c.506T>A) in the general population?

CMTM4 p.Phe169Tyr (c.506T>A) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about CMTM4 p.Phe169Tyr (c.506T>A)?

AlphaMissense predicts likely benign (score 0.1401) — an in-silico prediction, not a clinical call.

CMTM4 p.Phe169Tyr

c.506T>A · VCV3267999

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1401 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1401	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -5.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 74 kb · p 0.077 · regional, not allelic
Overall
CADD	20.2	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

Grpmax group 0.00153% European (non-Finnish) · 18/1,180,002 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00112% 18/1,613,884 alleles · very rare

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.Phe169Tyr
Coding: c.506T>A
MANE Select: NM_181521
Type: single nucleotide variant
Location: chr16:66622179 (GRCh38)
Gene constraint: LOEUF 1.136 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.82
Residue 169: the marvel domain

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-phe169tyr (accessed [today's date]).

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