Is GRHL3 p.Arg409= (c.1227C>T) pathogenic?

GRHL3 p.Arg409= (c.1227C>T) is classified Likely benign in GRHL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-25). Very rare (popmax 0.004%, afr); Associated with van der Woude syndrome 2.

What condition is associated with GRHL3 p.Arg409= (c.1227C>T)?

GRHL3 p.Arg409= (c.1227C>T) is associated with van der Woude syndrome 2 (ClinVar).

How common is GRHL3 p.Arg409= (c.1227C>T) in the general population?

GRHL3 p.Arg409= (c.1227C>T) is very rare (popmax 0.004%, afr) (gnomAD).

GRHL3 p.Arg409=

c.1227C>T · rs145324418 · VCV2714323

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

van der Woude syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.2	GERP -3.7
Overall
CADD	4.349	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,924 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000805% 13/1,614,056 alleles · very rare exomes 11/1,461,866 · genomes 2/152,190 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,975
East Asian	0.00223%	44,884
Admixed American	0.00167%	60,006
South Asian	0.0011%	91,090
European (non-Finnish)	0.000593%	168,575

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: GRHL3
Protein: p.Arg409=
Coding: c.1227C>T
MANE Select: NM_198173
dbSNP: rs145324418
Type: single nucleotide variant
Location: chr1:24342714 (GRCh38)
Gene constraint: LOEUF 0.4 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.27
Residue 409: the grh/cp2 db domain

Full GRHL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

van der Woude syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GRHL3 p.Arg409Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
GRHL3 p.Arg391Cys Pathogenic/Likely pathogenic ★★ same condition
GRHL3 p.Arg264Trp Uncertain significance ★★ ⚠ same condition
GRHL3 p.Arg417Gln Uncertain significance ★★ ⚠ same condition
GRHL3 p.Arg490Cys Uncertain significance ★★ ⚠ same condition
GRHL3 p.Pro147Ser Uncertain significance ★★ ⚠ same condition
GRHL3 p.Trp602Ter Uncertain significance ★★ same condition
GRHL3 c.204+13C>G Benign/Likely 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/grhl3-p-arg409 (accessed [today's date]).

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