Is CNNM4 p.Arg556Cys (c.1666C>T) pathogenic?

CNNM4 p.Arg556Cys (c.1666C>T) is classified Uncertain significance in CNNM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-13). AlphaMissense: likely pathogenic (0.8633); Very rare (popmax 0.0022%, sas).

How common is CNNM4 p.Arg556Cys (c.1666C>T) in the general population?

CNNM4 p.Arg556Cys (c.1666C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CNNM4 p.Arg556Cys (c.1666C>T)?

AlphaMissense predicts likely pathogenic (score 0.8633) — an in-silico prediction, not a clinical call.

CNNM4 p.Arg556Cys

c.1666C>T · rs767254813 · VCV1971149

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8633 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8633	likely pathogenic
REVEL	0.727	pathogenic-leaning
SaProt	LLR -13.39	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 12 kb · p 0.00035 · regional, not allelic
Overall
CADD	34.0	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

Grpmax group 0.0022% South Asian · 2/91,080 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000479% 7/1,461,760 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,540
Admixed American	0.00167%	60,022
African / African-American	0.00133%	75,058
European (non-Finnish)	0.000254%	393,345

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CNNM4
Protein: p.Arg556Cys
Coding: c.1666C>T
MANE Select: NM_020184
dbSNP: rs767254813
Type: single nucleotide variant
Location: chr2:96797632 (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

Similar variants

CNNM4 p.Arg556Pro Likely pathogenic ★ same residue
CNNM4 p.Arg556His Uncertain significance ★ ⚠ same residue
CNNM4 p.Arg519Ter Pathogenic ★★ same type
CNNM4 p.Arg605Ter Pathogenic ★★ same type
CNNM4 p.Gln564Ter Pathogenic ★★ same type
CNNM4 p.Gln717Ter Pathogenic/Likely pathogenic ★★ same type
CNNM4 c.2130+5G>A Uncertain significance ★★ same type
CNNM4 c.*1126G>A 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/cnnm4-p-arg556cys (accessed [today's date]).

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