Is CNNM4 p.Cys244Phe (c.731G>T) pathogenic?

CNNM4 p.Cys244Phe (c.731G>T) is classified Uncertain significance in CNNM4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-08-05). AlphaMissense: likely pathogenic (0.9736); Absent from gnomAD v4.1; Associated with retinitis pigmentosa.

What condition is associated with CNNM4 p.Cys244Phe (c.731G>T)?

CNNM4 p.Cys244Phe (c.731G>T) is associated with retinitis pigmentosa, Jalili syndrome (ClinVar).

How common is CNNM4 p.Cys244Phe (c.731G>T) in the general population?

CNNM4 p.Cys244Phe (c.731G>T) is absent from gnomAD v4.1 (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CNNM4 p.Cys244Phe (c.731G>T)?

AlphaMissense predicts likely pathogenic (score 0.9736) — an in-silico prediction, not a clinical call.

CNNM4 p.Cys244Phe

c.731G>T · rs1300890772 · VCV1297152

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9736 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.9736	likely pathogenic
REVEL	0.913	moderately pathogenic-leaning
SaProt	LLR -14.45	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 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 36 kb · p 1.3e-09 · regional, not allelic
Overall
CADD	32.0	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.Cys244Phe
Coding: c.731G>T
MANE Select: NM_020184
dbSNP: rs1300890772
Type: single nucleotide variant
Location: chr2:96761730 (GRCh38)
Gene constraint: LOEUF 0.794 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.20 · 6 PDB
Residue 244: the cnnm transmembrane domain

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

Disease context

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Jalili syndrome

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

CNNM4 p.Cys244Ser Uncertain significance ★★ ⚠ same residue
CNNM4 p.Arg519Ter Pathogenic ★★ same condition
CNNM4 p.Gln564Ter Pathogenic ★★ same condition
CNNM4 p.Gln717Ter Pathogenic/Likely pathogenic ★★ same condition
CNNM4 c.2130+5G>A Uncertain significance ★★ same condition
CNNM4 c.*1126G>A Uncertain significance ★★ same condition
CNNM4 p.Ala598Thr Uncertain significance ★★ ⚠ same condition
CNNM4 p.Arg523Gln 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-cys244phe (accessed [today's date]).

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