Is GRHL3 p.Pro423Ser (c.1267C>T) pathogenic?

GRHL3 p.Pro423Ser (c.1267C>T) is classified Uncertain significance in GRHL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.0827); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with GRHL3 p.Pro423Ser (c.1267C>T)?

GRHL3 p.Pro423Ser (c.1267C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GRHL3 p.Pro423Ser (c.1267C>T) in the general population?

GRHL3 p.Pro423Ser (c.1267C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about GRHL3 p.Pro423Ser (c.1267C>T)?

AlphaMissense predicts likely benign (score 0.0827) — an in-silico prediction, not a clinical call.

GRHL3 p.Pro423Ser

c.1267C>T · rs766633283 · VCV2531583

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0827 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0827	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -5.51	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 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 18 kb · p 2.2e-08 · regional, not allelic
Overall
CADD	20.2	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 0.004% African / African-American · 3/74,918 alleles

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

Overall 0.000743% 12/1,614,032 alleles · very rare exomes 10/1,461,870 · genomes 2/152,162 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,973
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.000678%	147,502

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.Pro423Ser
Coding: c.1267C>T
MANE Select: NM_198173
dbSNP: rs766633283
Type: single nucleotide variant
Location: chr1:24342754 (GRCh38)
Gene constraint: LOEUF 0.4 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.27
Residue 423: the grh/cp2 db domain

Full GRHL3 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

GRHL3 p.Arg191His Uncertain significance ★★ ⚠ same condition
GRHL3 p.Arg264Trp Uncertain significance ★★ ⚠ same condition
GRHL3 p.Met47Thr Uncertain significance ★★ ⚠ same condition
GRHL3 p.Pro147Ser Uncertain significance ★★ ⚠ same condition
GRHL3 c.1047+1G>A Pathogenic ★ same condition
GRHL3 p.Gln312Ter Pathogenic ★ same condition
GRHL3 p.Leu599Val Likely pathogenic ★ same condition
GRHL3 p.Ala138Val 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/grhl3-p-pro423ser (accessed [today's date]).

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