Is ALX4 p.Ala243Val (c.728C>T) pathogenic?

ALX4 p.Ala243Val (c.728C>T) is classified Conflicting classifications of pathogenicity in ALX4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-14). AlphaMissense: likely pathogenic (0.6202); Ultra-rare (popmax 0.085%, amr); Associated with Inborn genetic diseases.

What condition is associated with ALX4 p.Ala243Val (c.728C>T)?

ALX4 p.Ala243Val (c.728C>T) is associated with Inborn genetic diseases, parietal foramina 2 (ClinVar).

How common is ALX4 p.Ala243Val (c.728C>T) in the general population?

ALX4 p.Ala243Val (c.728C>T) is ultra-rare (popmax 0.085%, amr) (gnomAD).

What do computational predictors say about ALX4 p.Ala243Val (c.728C>T)?

AlphaMissense predicts likely pathogenic (score 0.6202) — an in-silico prediction, not a clinical call.

ALX4 p.Ala243Val

c.728C>T · rs145166164 · VCV304705

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6202 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.085%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6202	likely pathogenic
REVEL	0.612	indeterminate
SaProt	LLR -9.86	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP -2.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 45 kb · p 0.71 · regional, not allelic
Overall
CADD	23.9	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 0.085% Admixed American · 51/60,012 alleles

Filtering AF 0.0663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0598%

Overall 0.00793% 128/1,614,084 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.085%	1,177
African / African-American	0.0467%	2,141
East Asian	0.0178%	5,612
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00229%	43,705
South Asian	0.0022%	45,545

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.Ala243Val
Coding: c.728C>T
MANE Select: NM_021926
dbSNP: rs145166164
Type: single nucleotide variant
Location: chr11:44275397 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.00 · 4 PDB
Residue 243: a DNA-binding region; an α-helix

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

Also linked: parietal foramina 2

Similar variants

ALX4 p.Ala243= Benign ★★ same residue
ALX4 p.Arg265Ter Pathogenic ★★ same condition
ALX4 c.*2991G>A Uncertain significance ★★ 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

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-ala243val (accessed [today's date]).

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