Is CNNM3 p.Ile441Thr (c.1322T>C) pathogenic?

CNNM3 p.Ile441Thr (c.1322T>C) is classified Uncertain significance in CNNM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-26). AlphaMissense: likely pathogenic (0.8569); Absent from gnomAD v4.1.

How common is CNNM3 p.Ile441Thr (c.1322T>C) in the general population?

CNNM3 p.Ile441Thr (c.1322T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNNM3 p.Ile441Thr (c.1322T>C)?

AlphaMissense predicts likely pathogenic (score 0.8569) — an in-silico prediction, not a clinical call.

CNNM3 p.Ile441Thr

c.1322T>C · rs2466566209 · VCV2257188

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8569 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8569	likely pathogenic
REVEL	0.98	strongly pathogenic-leaning
SaProt	LLR -14.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 15 kb · p 0.00086 · regional, not allelic
Overall
CADD	28.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CNNM3
Protein: p.Ile441Thr
Coding: c.1322T>C
MANE Select: NM_017623
dbSNP: rs2466566209
Type: single nucleotide variant
Location: chr2:96825154 (GRCh38)
Gene constraint: LOEUF 1.23 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.63 · 7 PDB
Residue 441: 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-ile441thr (accessed [today's date]).

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