Is CMTM2 p.Arg69Pro (c.206G>C) pathogenic?

CMTM2 p.Arg69Pro (c.206G>C) is classified Uncertain significance in CMTM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: ambiguous (0.3627); Very rare (popmax 0.00203%, nfe).

How common is CMTM2 p.Arg69Pro (c.206G>C) in the general population?

CMTM2 p.Arg69Pro (c.206G>C) is very rare (popmax 0.00203%, nfe) (gnomAD).

What do computational predictors say about CMTM2 p.Arg69Pro (c.206G>C)?

AlphaMissense predicts ambiguous (score 0.3627) — an in-silico prediction, not a clinical call.

CMTM2 p.Arg69Pro

c.206G>C · VCV4230503

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3627 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3627	ambiguous
REVEL	0.222	benign-leaning
SaProt	LLR -9.33	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 0.037	GERP -0.3
Regional constraint	o/e 0.89	unconstrained · MANE · 8,508 bp · p 0.043 · regional, not allelic
Overall
CADD	22.6	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 0.00203% European (non-Finnish) · 24/1,180,030 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00161% 26/1,613,712 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00203%	49,168
Remaining individualsnot grpmax-eligible	0.0016%	62,464
African / African-American	0.00134%	74,748

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: CMTM2
Protein: p.Arg69Pro
Coding: c.206G>C
MANE Select: NM_144673
Type: single nucleotide variant
Location: chr16:66579813 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.74

Full CMTM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CMTM2 p.Ala181Ser Uncertain significance ★ ⚠ same type
CMTM2 p.Ala181Val Uncertain significance ★ ⚠ same type
CMTM2 p.Ala88Thr Uncertain significance ★ ⚠ same type
CMTM2 p.Ala9Thr Uncertain significance ★ ⚠ same type
CMTM2 p.Arg171Gln Uncertain significance ★ ⚠ same type
CMTM2 p.Arg171Trp Uncertain significance ★ ⚠ same type
CMTM2 p.Arg70Cys Uncertain significance ★ ⚠ same type
CMTM2 p.Asn201Ser 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/cmtm2-p-arg69pro (accessed [today's date]).

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