Is GRHL2 p.Ser463Arg (c.1389T>A) pathogenic?

GRHL2 p.Ser463Arg (c.1389T>A) is classified Uncertain significance in GRHL2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.7741); Very rare (popmax 0.00212%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GRHL2 p.Ser463Arg (c.1389T>A)?

GRHL2 p.Ser463Arg (c.1389T>A) is associated with Inborn genetic diseases (ClinVar).

How common is GRHL2 p.Ser463Arg (c.1389T>A) in the general population?

GRHL2 p.Ser463Arg (c.1389T>A) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about GRHL2 p.Ser463Arg (c.1389T>A)?

AlphaMissense predicts likely pathogenic (score 0.7741) — an in-silico prediction, not a clinical call.

GRHL2 p.Ser463Arg

c.1389T>A · rs763171411 · VCV2497851

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7741 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7741	likely pathogenic
REVEL	0.187	benign-leaning
SaProt	LLR -8.48	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.5	GERP -5.1
Regional constraint	o/e 0.82	unconstrained · MANE · 35 kb · p 0.0051 · regional, not allelic
Overall
CADD	13.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00212% European (non-Finnish) · 25/1,179,848 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00155% 25/1,613,670 alleles · very rare exomes 21/1,461,710 · genomes 4/151,960 · joint denominator

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: GRHL2
Protein: p.Ser463Arg
Coding: c.1389T>A
MANE Select: NM_024915
dbSNP: rs763171411
Type: single nucleotide variant
Location: chr8:101632269 (GRCh38)
Gene constraint: LOEUF 0.367 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.46 · 1 PDB
Residue 463: the grh/cp2 db domain

Full GRHL2 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

GRHL2 p.Ala46Thr Uncertain significance ★★ ⚠ same condition
GRHL2 p.Arg229Gln Uncertain significance ★★ ⚠ same condition
GRHL2 p.Arg290Leu Uncertain significance ★★ ⚠ same condition
GRHL2 p.Arg401His Uncertain significance ★★ ⚠ same condition
GRHL2 p.Arg434Ser Uncertain significance ★★ ⚠ same condition
GRHL2 p.Arg513Gln Uncertain significance ★★ ⚠ same condition
GRHL2 p.Ile369Val Uncertain significance ★★ ⚠ same condition
GRHL2 p.Leu107Met 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/grhl2-p-ser463arg (accessed [today's date]).

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