Is ALX1 p.Phe8Ser (c.23T>C) pathogenic?

ALX1 p.Phe8Ser (c.23T>C) is classified Uncertain significance in ALX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-24). AlphaMissense: ambiguous (0.5283); Very rare (popmax 6.84e-05%); Associated with Inborn genetic diseases.

What condition is associated with ALX1 p.Phe8Ser (c.23T>C)?

ALX1 p.Phe8Ser (c.23T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ALX1 p.Phe8Ser (c.23T>C) in the general population?

ALX1 p.Phe8Ser (c.23T>C) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about ALX1 p.Phe8Ser (c.23T>C)?

AlphaMissense predicts ambiguous (score 0.5283) — an in-silico prediction, not a clinical call.

ALX1 p.Phe8Ser

c.23T>C · rs1435940451 · VCV2296624

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5283 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5283	ambiguous
REVEL	0.585	indeterminate
SaProt	LLR -4.91	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 3,585 bp · p 0.071 · regional, not allelic
Overall
CADD	27.0	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

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,296 alleles · very rare

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: ALX1
Protein: p.Phe8Ser
Coding: c.23T>C
MANE Select: NM_006982
dbSNP: rs1435940451
Type: single nucleotide variant
Location: chr12:85280284 (GRCh38)
Gene constraint: LOEUF 0.838 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.32

Full ALX1 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

ALX1 p.Arg257Pro Uncertain significance ★★ ⚠ same condition
ALX1 p.Val50Ala Uncertain significance ★★ ⚠ same condition
ALX1 p.Leu119Arg Likely benign ★★ same condition
ALX1 p.Ala185Val Uncertain significance ★ ⚠ same condition
ALX1 p.Arg188Ser Uncertain significance ★ ⚠ same condition
ALX1 p.Arg257Trp Uncertain significance ★ ⚠ same condition
ALX1 p.Arg64Ser Uncertain significance ★ ⚠ same condition
ALX1 p.Arg94Gly 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/alx1-p-phe8ser (accessed [today's date]).

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