Is IRF6 p.Pro203Ser (c.607C>T) pathogenic?

IRF6 p.Pro203Ser (c.607C>T) is classified Uncertain significance in IRF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-22). AlphaMissense: likely benign (0.0871); Very rare (popmax 0.00891%, eas); Associated with Inborn genetic diseases.

What condition is associated with IRF6 p.Pro203Ser (c.607C>T)?

IRF6 p.Pro203Ser (c.607C>T) is associated with Inborn genetic diseases (ClinVar).

How common is IRF6 p.Pro203Ser (c.607C>T) in the general population?

IRF6 p.Pro203Ser (c.607C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about IRF6 p.Pro203Ser (c.607C>T)?

AlphaMissense predicts likely benign (score 0.0871) — an in-silico prediction, not a clinical call.

IRF6 p.Pro203Ser

c.607C>T · rs774616831 · VCV2605449

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0871 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0871	likely benign
REVEL	0.355	indeterminate
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 4,124 bp · p 0.14 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,902 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000496% 8/1,614,078 alleles · very rare exomes 7/1,461,866 · genomes 1/152,212 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,225
European (non-Finnish)	0.000339%	295,004

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.Pro203Ser
Coding: c.607C>T
MANE Select: NM_006147
dbSNP: rs774616831
Type: single nucleotide variant
Location: chr1:209792329 (GRCh38)
Gene constraint: LOEUF 0.214 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.19

Full IRF6 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

IRF6 p.Pro203Thr Uncertain significance ★ ⚠ same residue
IRF6 c.1060+1G>A Pathogenic/Likely pathogenic ★★ same condition
IRF6 p.Asn94Ser Uncertain significance ★★ ⚠ same condition
IRF6 p.Leu336Arg Uncertain significance ★★ same condition
IRF6 p.Ser424Leu Likely pathogenic ★ ⚠ same condition
IRF6 p.Asn431Thr Uncertain significance ★ ⚠ same condition
IRF6 p.Asp135Gly Uncertain significance ★ ⚠ same condition
IRF6 p.Asp140Gly 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/irf6-p-pro203ser (accessed [today's date]).

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