Is CNNM2 p.Val371Leu (c.1111G>C) pathogenic?

CNNM2 p.Val371Leu (c.1111G>C) is classified Uncertain significance in CNNM2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-06-29). AlphaMissense: likely pathogenic (0.9858); Absent from gnomAD v4.1; Associated with Neurodevelopmental abnormality.

What condition is associated with CNNM2 p.Val371Leu (c.1111G>C)?

CNNM2 p.Val371Leu (c.1111G>C) is associated with Neurodevelopmental abnormality (ClinVar).

How common is CNNM2 p.Val371Leu (c.1111G>C) in the general population?

CNNM2 p.Val371Leu (c.1111G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNNM2 p.Val371Leu (c.1111G>C)?

AlphaMissense predicts likely pathogenic (score 0.9858) — an in-silico prediction, not a clinical call.

CNNM2 p.Val371Leu

c.1111G>C · rs1845549561 · VCV984578

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9858 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Neurodevelopmental abnormality

Computational evidence

Protein change
AlphaMissense	0.9858	likely pathogenic
REVEL	0.633	indeterminate
SaProt	LLR -10.89	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 0.7, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 412 bp · p 2.8e-23 · regional, not allelic
Overall
CADD	29.3	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: CNNM2
Protein: p.Val371Leu
Coding: c.1111G>C
MANE Select: NM_017649
dbSNP: rs1845549561
Type: single nucleotide variant
Location: chr10:102919591 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 7 PDB
Residue 371: the cnnm transmembrane domain

Full CNNM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Neurodevelopmental abnormality — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNNM2 p.Arg602Ter Likely pathogenic ★★ same type
CNNM2 p.Asn327Ser Likely pathogenic ★★ same type
CNNM2 p.Glu122Lys Pathogenic/Likely pathogenic ★★ same type
CNNM2 p.Glu357Lys Pathogenic ★★ same type
CNNM2 p.Ser269Trp Pathogenic/Likely pathogenic ★★ same type
CNNM2 c.1904-6C>G Uncertain significance ★★ same type
CNNM2 p.Ala44Val Uncertain significance ★★ same type
CNNM2 p.Ala45Glu 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/cnnm2-p-val371leu (accessed [today's date]).

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