Is CMTM4 p.Arg200Cys (c.598C>T) pathogenic?

CMTM4 p.Arg200Cys (c.598C>T) is classified Uncertain significance in CMTM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: likely benign (0.1985); Very rare (popmax 0.0046%, eas).

How common is CMTM4 p.Arg200Cys (c.598C>T) in the general population?

CMTM4 p.Arg200Cys (c.598C>T) is very rare (popmax 0.0046%, eas) (gnomAD).

What do computational predictors say about CMTM4 p.Arg200Cys (c.598C>T)?

AlphaMissense predicts likely benign (score 0.1985) — an in-silico prediction, not a clinical call.

CMTM4 p.Arg200Cys

c.598C>T · rs138396334 · VCV2370789

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1985 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0046%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1985	likely benign
REVEL	0.301	indeterminate
SaProt	LLR -8.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL 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 0.34	constrained · MANE · 38 bp · p 0.0029 · regional, not allelic
Overall
CADD	29.2	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 0.0046% East Asian · 2/43,508 alleles

Filtering AF 0.000917% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000615%

Overall 0.00133% 21/1,579,720 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0046%	21,754
South Asian	0.00345%	28,961
African / African-American	0.00134%	74,440
European (non-Finnish)	0.00129%	77,464

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.Arg200Cys
Coding: c.598C>T
MANE Select: NM_181521
dbSNP: rs138396334
Type: single nucleotide variant
Location: chr16:66622087 (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 p.Arg200His Uncertain significance ★ ⚠ same residue
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.Arg205Cys Uncertain significance ★ ⚠ same type
CMTM4 p.Asn185Ser 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-arg200cys (accessed [today's date]).

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