Is ALX4 p.Cys331Tyr (c.992G>A) pathogenic?

ALX4 p.Cys331Tyr (c.992G>A) is classified Uncertain significance in ALX4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-18). AlphaMissense: likely pathogenic (0.9061); Ultra-rare (popmax 0.015%, amr); Associated with Inborn genetic diseases.

What condition is associated with ALX4 p.Cys331Tyr (c.992G>A)?

ALX4 p.Cys331Tyr (c.992G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ALX4 p.Cys331Tyr (c.992G>A) in the general population?

ALX4 p.Cys331Tyr (c.992G>A) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about ALX4 p.Cys331Tyr (c.992G>A)?

AlphaMissense predicts likely pathogenic (score 0.9061) — an in-silico prediction, not a clinical call.

ALX4 p.Cys331Tyr

c.992G>A · rs980674490 · VCV806649

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9061 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9061	likely pathogenic
REVEL	0.804	moderately pathogenic-leaning
SaProt	LLR -5.67	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 45 kb · p 0.71 · regional, not allelic
Overall
CADD	27.6	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 0.015% Admixed American · 9/59,974 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.000682% 11/1,612,480 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,664
European (non-Finnish)	0.00017%	589,870

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: ALX4
Protein: p.Cys331Tyr
Coding: c.992G>A
MANE Select: NM_021926
dbSNP: rs980674490
Type: single nucleotide variant
Location: chr11:44265098 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.00 · 4 PDB

Full ALX4 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

ALX4 p.Arg265Ter Pathogenic ★★ same condition
ALX4 p.Arg193Gln Uncertain significance ★★ ⚠ same condition
ALX4 p.Arg257His Uncertain significance ★★ ⚠ same condition
ALX4 p.Arg388His Uncertain significance ★★ ⚠ same condition
ALX4 p.Asp176Gly Uncertain significance ★★ ⚠ same condition
ALX4 p.Asp206Asn Uncertain significance ★★ ⚠ same condition
ALX4 p.Gln104Pro Uncertain significance ★★ ⚠ same condition
ALX4 p.Gln98Lys 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/alx4-p-cys331tyr (accessed [today's date]).

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