Is CNNM4 p.Ala554Ser (c.1660G>T) pathogenic?

CNNM4 p.Ala554Ser (c.1660G>T) is classified Uncertain significance in CNNM4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-03). AlphaMissense: ambiguous (0.3686); Very rare (popmax 0.00932%, nfe).

How common is CNNM4 p.Ala554Ser (c.1660G>T) in the general population?

CNNM4 p.Ala554Ser (c.1660G>T) is very rare (popmax 0.00932%, nfe) (gnomAD).

What do computational predictors say about CNNM4 p.Ala554Ser (c.1660G>T)?

AlphaMissense predicts ambiguous (score 0.3686) — an in-silico prediction, not a clinical call.

CNNM4 p.Ala554Ser

c.1660G>T · rs764294792 · VCV1518188

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3686 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00932%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3686	ambiguous
REVEL	0.361	indeterminate
SaProt	LLR -8.79	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP -0.24, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 12 kb · p 0.00035 · regional, not allelic
Overall
CADD	25.9	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

Grpmax group 0.00932% European (non-Finnish) · 110/1,180,042 alleles

Filtering AF 0.0079% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.007% 113/1,613,934 alleles · very rare exomes 106/1,461,788 · genomes 7/152,146 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00932%	10,728
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-American	0.00133%	74,914

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.Ala554Ser
Coding: c.1660G>T
MANE Select: NM_020184
dbSNP: rs764294792
Type: single nucleotide variant
Location: chr2:96797626 (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.Ala554Thr Uncertain significance ★ ⚠ same residue
CNNM4 p.Ala554Val 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-ala554ser (accessed [today's date]).

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