Is CNNM3 p.Val440Met (c.1318G>A) pathogenic?

CNNM3 p.Val440Met (c.1318G>A) is classified Uncertain significance in CNNM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-27). AlphaMissense: likely pathogenic (0.8797); Ultra-rare (popmax 0.0117%, amr).

How common is CNNM3 p.Val440Met (c.1318G>A) in the general population?

CNNM3 p.Val440Met (c.1318G>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about CNNM3 p.Val440Met (c.1318G>A)?

AlphaMissense predicts likely pathogenic (score 0.8797) — an in-silico prediction, not a clinical call.

CNNM3 p.Val440Met

c.1318G>A · rs201849374 · VCV2489787

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8797 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8797	likely pathogenic
REVEL	0.904	moderately pathogenic-leaning
SaProt	LLR -13.67	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.28	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 8.6	GERP 0.88, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 15 kb · p 0.00086 · regional, not allelic
Overall
CADD	29.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0117% Admixed American · 7/60,012 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00198% 32/1,614,040 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,573
East Asian	0.00223%	44,876
European (non-Finnish)	0.00186%	53,638
Remaining individualsnot grpmax-eligible	0.0016%	62,484
South Asian	0.0011%	91,086

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.Val440Met
Coding: c.1318G>A
MANE Select: NM_017623
dbSNP: rs201849374
Type: single nucleotide variant
Location: chr2:96825150 (GRCh38)
Gene constraint: LOEUF 1.23 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.63 · 7 PDB
Residue 440: an α-helix; the cbs 2 domain

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-val440met (accessed [today's date]).

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