Is GRHL3 p.Ser477= (c.1431G>A) pathogenic?

GRHL3 p.Ser477= (c.1431G>A) is classified Likely benign in GRHL3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-08-19). Ultra-rare (popmax 0.0111%, eas); Associated with GRHL3-related disorder.

What condition is associated with GRHL3 p.Ser477= (c.1431G>A)?

GRHL3 p.Ser477= (c.1431G>A) is associated with GRHL3-related disorder (ClinVar).

How common is GRHL3 p.Ser477= (c.1431G>A) in the general population?

GRHL3 p.Ser477= (c.1431G>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

GRHL3 p.Ser477=

c.1431G>A · rs376734823 · VCV3030352

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Conditions

GRHL3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.5	GERP -3.4
Overall
CADD	1.549	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,886 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.0018% 29/1,613,302 alleles · ultra-rare exomes 24/1,461,574 · genomes 5/151,728 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,977
African / African-American	0.00536%	18,672
South Asian	0.00329%	30,359
European (non-Finnish)	0.00144%	69,395

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.Ser477=
Coding: c.1431G>A
MANE Select: NM_198173
dbSNP: rs376734823
Type: single nucleotide variant
Location: chr1:24344908 (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

GRHL3-related disorder

Similar variants

GRHL3 p.Ser477Leu Benign ★★ same residue
GRHL3 p.Pro39Leu Uncertain significance ★★ ⚠ same condition
GRHL3 p.Glu498Ter Likely pathogenic ★ same condition
GRHL3 p.Arg313Pro Uncertain significance ★ ⚠ same condition
GRHL3 p.Asp288His Uncertain significance ★ ⚠ same condition
GRHL3 p.His464Gln Uncertain significance ★ ⚠ same condition
GRHL3 p.Met570Val Uncertain significance ★ same condition
GRHL3 p.Lys199Glu 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-ser477 (accessed [today's date]).

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