Is IRF6 p.Ala2Val (c.5C>T) pathogenic?

IRF6 p.Ala2Val (c.5C>T) is classified Pathogenic in IRF6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2003-10-01). AlphaMissense: ambiguous (0.4716); Absent from gnomAD v4.1; Associated with van der Woude syndrome 1.

What condition is associated with IRF6 p.Ala2Val (c.5C>T)?

IRF6 p.Ala2Val (c.5C>T) is associated with van der Woude syndrome 1 (ClinVar).

How common is IRF6 p.Ala2Val (c.5C>T) in the general population?

IRF6 p.Ala2Val (c.5C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IRF6 p.Ala2Val (c.5C>T)?

AlphaMissense predicts ambiguous (score 0.4716) — an in-silico prediction, not a clinical call.

IRF6 p.Ala2Val

c.5C>T · rs28942093 · VCV3416

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4716 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

van der Woude syndrome 1

Computational evidence

Protein change
AlphaMissense	0.4716	ambiguous
REVEL	0.774	moderately pathogenic-leaning
SaProt	LLR -8.74	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 4,991 bp · p 1.5e-12 · regional, not allelic
Overall
CADD	26.9	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

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: IRF6
Protein: p.Ala2Val
Coding: c.5C>T
MANE Select: NM_006147
dbSNP: rs28942093
Type: single nucleotide variant
Location: chr1:209801409 (GRCh38)
Gene constraint: LOEUF 0.214 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.19
Residue 2: a UniProt-annotated variant site (in vws1)

Full IRF6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

van der Woude syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IRF6 p.Ala2Thr Uncertain significance ★ ⚠ same residue
IRF6 p.Arg250Ter Pathogenic ★★ same condition
IRF6 p.Arg400Trp Pathogenic ★★ same condition
IRF6 p.Arg412Ter Pathogenic ★★ same condition
IRF6 p.Arg6Cys Pathogenic/Likely pathogenic ★★ same condition
IRF6 p.Arg84His Pathogenic ★★ same condition
IRF6 p.Arg9Trp Pathogenic/Likely pathogenic ★★ same condition
IRF6 p.Gln287Ter Pathogenic/Likely pathogenic ★★ 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/irf6-p-ala2val (accessed [today's date]).

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