Is CNNM3 p.Ala685Val (c.2054C>T) pathogenic?

CNNM3 p.Ala685Val (c.2054C>T) is classified Uncertain significance in CNNM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-29). AlphaMissense: likely benign (0.0789); Ultra-rare (popmax 0.0111%, eas).

How common is CNNM3 p.Ala685Val (c.2054C>T) in the general population?

CNNM3 p.Ala685Val (c.2054C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about CNNM3 p.Ala685Val (c.2054C>T)?

AlphaMissense predicts likely benign (score 0.0789) — an in-silico prediction, not a clinical call.

CNNM3 p.Ala685Val

c.2054C>T · VCV4004332

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0789 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0789	likely benign
REVEL	0.316	indeterminate
SaProt	LLR -7.27	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 0.52	GERP 0.56, phastCons 0.001
Regional constraint	o/e 0.86	unconstrained · MANE · 15 kb · p 0.00086 · regional, not allelic
Overall
CADD	14.67	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 0.0111% East Asian · 5/44,878 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000806% 13/1,613,632 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,976
South Asian	0.00439%	22,766
African / African-American	0.00134%	74,868
European (non-Finnish)	0.000254%	393,314

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.Ala685Val
Coding: c.2054C>T
MANE Select: NM_017623
Type: single nucleotide variant
Location: chr2:96829129 (GRCh38)
Gene constraint: LOEUF 1.23 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.63 · 7 PDB
Residue 685: the 'disordered' region

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

Similar variants

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
CNNM3 p.Ala191Thr 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-ala685val (accessed [today's date]).

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