Is GRHL3 p.Ser237Phe (c.710C>T) pathogenic?

GRHL3 p.Ser237Phe (c.710C>T) is classified Uncertain significance in GRHL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-13). AlphaMissense: likely pathogenic (0.9547); Absent from gnomAD v4.1; Associated with van der Woude syndrome 2.

What condition is associated with GRHL3 p.Ser237Phe (c.710C>T)?

GRHL3 p.Ser237Phe (c.710C>T) is associated with van der Woude syndrome 2 (ClinVar).

How common is GRHL3 p.Ser237Phe (c.710C>T) in the general population?

GRHL3 p.Ser237Phe (c.710C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GRHL3 p.Ser237Phe (c.710C>T)?

AlphaMissense predicts likely pathogenic (score 0.9547) — an in-silico prediction, not a clinical call.

GRHL3 p.Ser237Phe

c.710C>T · VCV4279866

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9547 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

van der Woude syndrome 2

Computational evidence

Protein change
AlphaMissense	0.9547	likely pathogenic
REVEL	0.465	indeterminate
SaProt	LLR -10.95	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 18 kb · p 2.2e-08 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: GRHL3
Protein: p.Ser237Phe
Coding: c.710C>T
MANE Select: NM_198173
Type: single nucleotide variant
Location: chr1:24337659 (GRCh38)
Gene constraint: LOEUF 0.4 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.27
Residue 237: 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.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-ser237phe (accessed [today's date]).

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