Is GRHL3 p.Pro579Ser (c.1735C>T) pathogenic?

GRHL3 p.Pro579Ser (c.1735C>T) is classified Uncertain significance in GRHL3 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.0762); Rare (popmax 0.1%, mid); Associated with van der Woude syndrome 2.

What condition is associated with GRHL3 p.Pro579Ser (c.1735C>T)?

GRHL3 p.Pro579Ser (c.1735C>T) is associated with van der Woude syndrome 2 (ClinVar).

How common is GRHL3 p.Pro579Ser (c.1735C>T) in the general population?

GRHL3 p.Pro579Ser (c.1735C>T) is rare (popmax 0.1%, mid) (gnomAD).

What do computational predictors say about GRHL3 p.Pro579Ser (c.1735C>T)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

GRHL3 p.Pro579Ser

c.1735C>T · VCV3352906

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.1%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

van der Woude syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -5.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.72	GERP -2.2
Overall
CADD	0.233	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 0.1% Middle Eastern · 6/5,976 alleles

Filtering AF 0.0437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.00427% 66/1,544,672 alleles · rare exomes 50/1,392,328 · genomes 16/152,344 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.1%	996
Admixed American	0.016%	6,262
African / African-American	0.0123%	8,102
Remaining individualsnot grpmax-eligible	0.00668%	14,975
European (non-Finnish)	0.00341%	29,347

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.Pro579Ser
Coding: c.1735C>T
MANE Select: NM_198173 · reported on NM_198174
Type: single nucleotide variant
Location: chr1:24364225 (GRCh38)
Gene constraint: LOEUF 0.4 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.27

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.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
GRHL3 c.686+13C>T 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-pro579ser (accessed [today's date]).

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