Is CNNM2 p.Glu174Val (c.521A>T) pathogenic?

CNNM2 p.Glu174Val (c.521A>T) is classified Uncertain significance in CNNM2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-01). AlphaMissense: likely pathogenic (0.816); Absent from gnomAD v4.1; Associated with CNNM2-related disorder.

What condition is associated with CNNM2 p.Glu174Val (c.521A>T)?

CNNM2 p.Glu174Val (c.521A>T) is associated with CNNM2-related disorder (ClinVar).

How common is CNNM2 p.Glu174Val (c.521A>T) in the general population?

CNNM2 p.Glu174Val (c.521A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNNM2 p.Glu174Val (c.521A>T)?

AlphaMissense predicts likely pathogenic (score 0.816) — an in-silico prediction, not a clinical call.

CNNM2 p.Glu174Val

c.521A>T · VCV3346183

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.816 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CNNM2-related disorder

Computational evidence

Protein change
AlphaMissense	0.816	likely pathogenic
REVEL	0.452	indeterminate
SaProt	LLR -8.63	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 0.18, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 310 bp · p 2.5e-05 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

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.Glu174Val
Coding: c.521A>T
MANE Select: NM_017649
Type: single nucleotide variant
Location: chr10:102919001 (GRCh38)
Gene constraint: LOEUF 0.312 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 7 PDB

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

Disease context

CNNM2-related disorder

Similar variants

CNNM2 p.Arg38Trp Uncertain significance ★★ ⚠ same condition
CNNM2 p.Lys667Arg Uncertain significance ★ ⚠ same condition
CNNM2 p.Ser273Ile Uncertain significance ★ ⚠ same condition
CNNM2 c.1904-6C>A Likely benign same condition
NT5C2 p.Val512= Likely benign same condition
CNNM2 p.Arg47fs Likely pathogenic ★ same condition
CNNM2 p.Glu646fs Pathogenic ★ same condition
CNNM2 p.Arg630fs Uncertain significance same condition

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-glu174val (accessed [today's date]).

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