Is CNNM4 p.Ala722Pro (c.2164G>C) pathogenic?

CNNM4 p.Ala722Pro (c.2164G>C) is classified Uncertain significance in CNNM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-24). AlphaMissense: likely pathogenic (0.9886); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CNNM4 p.Ala722Pro (c.2164G>C)?

CNNM4 p.Ala722Pro (c.2164G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CNNM4 p.Ala722Pro (c.2164G>C) in the general population?

CNNM4 p.Ala722Pro (c.2164G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNNM4 p.Ala722Pro (c.2164G>C)?

AlphaMissense predicts likely pathogenic (score 0.9886) — an in-silico prediction, not a clinical call.

CNNM4 p.Ala722Pro

c.2164G>C · VCV3834548

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9886 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9886	likely pathogenic
REVEL	0.533	indeterminate
SaProt	LLR -16.92	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 12 kb · p 0.00035 · regional, not allelic
Overall
CADD	26.0	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: CNNM4
Protein: p.Ala722Pro
Coding: c.2164G>C
MANE Select: NM_020184
Type: single nucleotide variant
Location: chr2:96809353 (GRCh38)
Gene constraint: LOEUF 0.794 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.20 · 6 PDB

Full CNNM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNNM4 p.Ala297Gly Uncertain significance ★★ ⚠ same condition
CNNM4 p.Ala35Thr Uncertain significance ★★ ⚠ same condition
CNNM4 p.Ala538Val Uncertain significance ★★ ⚠ same condition
CNNM4 p.Ala598Thr Uncertain significance ★★ ⚠ same condition
CNNM4 p.Ala635Thr Uncertain significance ★★ ⚠ same condition
CNNM4 p.Arg153Gln Uncertain significance ★★ ⚠ same condition
CNNM4 p.Arg178Lys Uncertain significance ★★ ⚠ same condition
CNNM4 p.Arg338Gly 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/cnnm4-p-ala722pro (accessed [today's date]).

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