Is CMTR2 p.His327Pro (c.980A>C) pathogenic?

CMTR2 p.His327Pro (c.980A>C) is classified Uncertain significance in CMTR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). AlphaMissense: likely benign (0.0972); Ultra-rare (popmax 0.0168%, nfe).

How common is CMTR2 p.His327Pro (c.980A>C) in the general population?

CMTR2 p.His327Pro (c.980A>C) is ultra-rare (popmax 0.0168%, nfe) (gnomAD).

What do computational predictors say about CMTR2 p.His327Pro (c.980A>C)?

AlphaMissense predicts likely benign (score 0.0972) — an in-silico prediction, not a clinical call.

CMTR2 p.His327Pro

c.980A>C · VCV4004085

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0972 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0972	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -10.63	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.047	GERP -4.7
Regional constraint	o/e 1.01	unconstrained · MANE · 2,309 bp · p 0.74 · regional, not allelic
Overall
CADD	15.54	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 0.0168% European (non-Finnish) · 198/1,179,994 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.0131% 211/1,614,034 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0168%	5,960
Remaining individualsnot grpmax-eligible	0.0112%	8,927
Admixed American	0.005%	20,001
African / African-American	0.004%	24,977

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: CMTR2
Protein: p.His327Pro
Coding: c.980A>C
MANE Select: NM_018348
Type: single nucleotide variant
Location: chr16:71284941 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.01

Full CMTR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CMTR2 p.Ala16Pro Uncertain significance ★ ⚠ same type
CMTR2 p.Ala16Thr Uncertain significance ★ ⚠ same type
CMTR2 p.Ala16Val Uncertain significance ★ ⚠ same type
CMTR2 p.Ala262Ser Uncertain significance ★ ⚠ same type
CMTR2 p.Ala31Ser Uncertain significance ★ ⚠ same type
CMTR2 p.Ala388Val Uncertain significance ★ ⚠ same type
CMTR2 p.Ala530Gly Uncertain significance ★ ⚠ same type
CMTR2 p.Ala684Thr 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/cmtr2-p-his327pro (accessed [today's date]).

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