Is IRF6 p.Arg91Ser (c.273A>T) pathogenic?

IRF6 p.Arg91Ser (c.273A>T) is classified Uncertain significance in IRF6 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9885); Absent from gnomAD v4.1; Associated with orofacial cleft 10.

What condition is associated with IRF6 p.Arg91Ser (c.273A>T)?

IRF6 p.Arg91Ser (c.273A>T) is associated with orofacial cleft 10 (ClinVar).

How common is IRF6 p.Arg91Ser (c.273A>T) in the general population?

IRF6 p.Arg91Ser (c.273A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IRF6 p.Arg91Ser (c.273A>T)?

AlphaMissense predicts likely pathogenic (score 0.9885) — an in-silico prediction, not a clinical call.

IRF6 p.Arg91Ser

c.273A>T · rs1553248262 · VCV559487

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9885 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

orofacial cleft 10

Computational evidence

Protein change
AlphaMissense	0.9885	likely pathogenic
REVEL	0.688	pathogenic-leaning
SaProt	LLR -9.36	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 -0.11	GERP -4.5, phastCons 0.55
Regional constraint	o/e 0.37	unconstrained · MANE · 4,991 bp · p 1.5e-12 · regional, not allelic
Overall
CADD	23.2	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.Arg91Ser
Coding: c.273A>T
MANE Select: NM_006147
dbSNP: rs1553248262
Type: single nucleotide variant
Location: chr1:209796454 (GRCh38)
Gene constraint: LOEUF 0.214 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.19
Residue 91: a DNA-binding region

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

Disease context

orofacial cleft 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IRF6 p.Glu199Lys Uncertain significance ⚠ same condition
IRF6 p.Pro172Ser Uncertain significance ⚠ same condition
IRF6 p.Val392Gly Uncertain significance ⚠ same condition
IRF6 p.Asp148Gly Benign same condition
IRF6 p.Gly121Val Benign same condition
IRF6 p.Leu391Phe Benign same condition
IRF6 p.Pro164Ala Benign same condition
IRF6 p.Ser153Ala 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/irf6-p-arg91ser (accessed [today's date]).

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