Is CNNM3 p.Arg10Trp (c.28C>T) pathogenic?

CNNM3 p.Arg10Trp (c.28C>T) is classified Uncertain significance in CNNM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: likely benign (0.0782); Ultra-rare (popmax 0.0754%, afr).

How common is CNNM3 p.Arg10Trp (c.28C>T) in the general population?

CNNM3 p.Arg10Trp (c.28C>T) is ultra-rare (popmax 0.0754%, afr) (gnomAD).

What do computational predictors say about CNNM3 p.Arg10Trp (c.28C>T)?

AlphaMissense predicts likely benign (score 0.0782) — an in-silico prediction, not a clinical call.

CNNM3 p.Arg10Trp

c.28C>T · rs373318478 · VCV2360773

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0782 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0754%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0782	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -7.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.59 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.062	GERP -2.8, phastCons 0.84
Regional constraint	o/e 1.16	unconstrained · MANE · 849 bp · p 0.0017 · regional, not allelic
Overall
CADD	13.09	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 0.0754% African / African-American · 49/64,954 alleles

Filtering AF 0.0586% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0526%

Overall 0.00637% 82/1,287,580 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0754%	1,326
Middle Eastern	0.0595%	1,680
Admixed American	0.0193%	5,176
South Asian	0.00519%	19,253
Remaining individualsnot grpmax-eligible	0.0042%	23,793
European (non-Finnish)	0.00216%	46,329

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: CNNM3
Protein: p.Arg10Trp
Coding: c.28C>T
MANE Select: NM_017623
dbSNP: rs373318478
Type: single nucleotide variant
Location: chr2:96816305 (GRCh38)
Gene constraint: LOEUF 1.23 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.63 · 7 PDB

Full CNNM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNNM3 p.Arg10Gly Uncertain significance ★ ⚠ same residue
CNNM3 p.Ala221Gly Uncertain significance ★★ ⚠ same type
CNNM3 p.Ala128Val Uncertain significance ★ ⚠ same type
CNNM3 p.Ala142Thr Uncertain significance ★ ⚠ same type
CNNM3 p.Ala146Val Uncertain significance ★ ⚠ same type
CNNM3 p.Ala158Thr Uncertain significance ★ ⚠ same type
CNNM3 p.Ala162Glu Uncertain significance ★ ⚠ same type
CNNM3 p.Ala176Thr 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/cnnm3-p-arg10trp (accessed [today's date]).

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