Is ALX4 p.Arg272Pro (c.815G>C) pathogenic?

ALX4 p.Arg272Pro (c.815G>C) is classified Pathogenic in ALX4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2000-12-01). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1; Associated with parietal foramina 2.

What condition is associated with ALX4 p.Arg272Pro (c.815G>C)?

ALX4 p.Arg272Pro (c.815G>C) is associated with parietal foramina 2 (ClinVar).

How common is ALX4 p.Arg272Pro (c.815G>C) in the general population?

ALX4 p.Arg272Pro (c.815G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALX4 p.Arg272Pro (c.815G>C)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

ALX4 p.Arg272Pro

c.815G>C · rs104894196 · VCV5017

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

parietal foramina 2

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic ✓ concordant with ClinVar · top 6% in ALX4
REVEL	0.94	strongly pathogenic-leaning
SaProt	LLR -15.44	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 2.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 45 kb · p 0.71 · regional, not allelic
Overall
CADD	33.0	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

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: ALX4
Protein: p.Arg272Pro
Coding: c.815G>C
MANE Select: NM_021926
dbSNP: rs104894196
Type: single nucleotide variant
Location: chr11:44267585 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.00 · 4 PDB
Residue 272: a DNA-binding region; a UniProt-annotated variant site (in pfm2); an α-helix

Full ALX4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

parietal foramina 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALX4 p.Arg272= Likely benign ★ same residue
ALX4 c.*2991G>A Uncertain significance ★★ same condition
ALX4 p.Arg388His Uncertain significance ★★ ⚠ same condition
ALX4 p.Pro116Arg Uncertain significance ★★ ⚠ same condition
ALX4 p.Pro190Leu Uncertain significance ★★ ⚠ same condition
ALX4 p.Pro92Arg Uncertain significance ★★ ⚠ same condition
ALX4 p.Ser207Leu Uncertain significance ★★ ⚠ same condition
ALX4 c.467-45T>C Benign ★★ 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-arg272pro (accessed [today's date]).

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