Is IRF6 p.Ser153= (c.459G>T) pathogenic?

IRF6 p.Ser153= (c.459G>T) is classified Benign in IRF6 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 56.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with autosomal dominant popliteal pterygium syndrome.

What condition is associated with IRF6 p.Ser153= (c.459G>T)?

IRF6 p.Ser153= (c.459G>T) is associated with autosomal dominant popliteal pterygium syndrome, van der Woude syndrome 1, orofacial cleft 6, susceptibility to (ClinVar).

IRF6 p.Ser153=

Q: How common is IRF6 p.Ser153= (c.459G>T) in the general population?

IRF6 p.Ser153= (c.459G>T) is common (popmax 56.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.459G>T · rs2013162 · VCV259925

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 56.8%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

autosomal dominant popliteal pterygium syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.6	GERP -4.6
Overall
CADD	0.293	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 56.8% East Asian · 25,504/44,870 alleles

Filtering AF 56.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 56%

Overall 38.3% 618,213/1,613,602 alleles · common exomes 562,690/1,461,512 · genomes 55,523/152,090 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	56.8%	2
Admixed American	53.8%	2
South Asian	41.3%	2
Amishnot grpmax-eligible	39.5%	3
Finnishnot grpmax-eligible	37.7%	3
European (non-Finnish)	37.6%	3
Remaining individualsnot grpmax-eligible	37.4%	3
Middle Eastern	32.4%	3
Ashkenazi Jewishnot grpmax-eligible	30.9%	3
African / African-American	27.8%	4

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: IRF6
Protein: p.Ser153=
Coding: c.459G>T
MANE Select: NM_006147
dbSNP: rs2013162
Type: single nucleotide variant
Location: chr1:209795339 (GRCh38)
Gene constraint: LOEUF 0.214 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.19
Residue 153: the 'disordered' region

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

Disease context

autosomal dominant popliteal pterygium syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: van der Woude syndrome 1 orofacial cleft 6, susceptibility to popliteal pterygium syndrome van der Woude syndrome

Similar variants

IRF6 p.Ser153Leu Uncertain significance ★ ⚠ same residue
IRF6 p.Ser153Ala Benign same residue
IRF6 c.1060+1G>A Pathogenic/Likely pathogenic ★★ same condition
IRF6 p.Arg250Gln Pathogenic/Likely pathogenic ★★ same condition
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

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-ser153 (accessed [today's date]).

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