Is GRHL2 p.Ser450Phe (c.1349C>T) pathogenic?

GRHL2 p.Ser450Phe (c.1349C>T) is classified Uncertain significance in GRHL2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-10). AlphaMissense: likely benign (0.11); Very rare (popmax 0.000434%); Associated with Inborn genetic diseases.

What condition is associated with GRHL2 p.Ser450Phe (c.1349C>T)?

GRHL2 p.Ser450Phe (c.1349C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GRHL2 p.Ser450Phe (c.1349C>T) in the general population?

GRHL2 p.Ser450Phe (c.1349C>T) is very rare (popmax 0.000434%) (gnomAD).

What do computational predictors say about GRHL2 p.Ser450Phe (c.1349C>T)?

AlphaMissense predicts likely benign (score 0.11) — an in-silico prediction, not a clinical call.

GRHL2 p.Ser450Phe

c.1349C>T · VCV3522544

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.11 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000434%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.11	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -8.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 35 kb · p 0.0051 · regional, not allelic
Overall
CADD	24.8	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 0.000434%

Overall 0.000434% 7/1,613,702 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,920
Remaining individualsnot grpmax-eligible	0.0032%	31,236

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser450Phe
Coding: c.1349C>T
MANE Select: NM_024915
Type: single nucleotide variant
Location: chr8:101632229 (GRCh38)
Gene constraint: LOEUF 0.367 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.46 · 1 PDB
Residue 450: the grh/cp2 db domain; the 'disordered' region

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.Ser450Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-ser450phe (accessed [today's date]).

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