Is GRHL2 p.Ser613Arg (c.1839C>A) pathogenic?

GRHL2 p.Ser613Arg (c.1839C>A) is classified Uncertain significance in GRHL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: ambiguous (0.4171); Very rare (popmax 0.00329%, sas).

How common is GRHL2 p.Ser613Arg (c.1839C>A) in the general population?

GRHL2 p.Ser613Arg (c.1839C>A) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about GRHL2 p.Ser613Arg (c.1839C>A)?

AlphaMissense predicts ambiguous (score 0.4171) — an in-silico prediction, not a clinical call.

GRHL2 p.Ser613Arg

c.1839C>A · VCV4808685

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4171 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4171	ambiguous
REVEL	0.146	moderately benign-leaning
SaProt	LLR -6.20	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 35 kb · p 0.0051 · regional, not allelic
Overall
CADD	21.0	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 0.00329% South Asian · 3/91,064 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000186% 3/1,613,374 alleles · very rare exomes 2/1,461,086 · genomes 1/152,288 · 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.Ser613Arg
Coding: c.1839C>A
MANE Select: NM_024915
Type: single nucleotide variant
Location: chr8:101666664 (GRCh38)
Gene constraint: LOEUF 0.367 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.46 · 1 PDB

Full GRHL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRHL2 p.Arg290Ter Pathogenic/Likely pathogenic ★★ same type
GRHL2 p.Arg426Ter Pathogenic/Likely pathogenic ★★ same type
GRHL2 p.Arg75Ter Pathogenic ★★ same type
GRHL2 c.1486-10T>G Uncertain significance ★★ same type
GRHL2 p.Ala148Thr Uncertain significance ★★ ⚠ same type
GRHL2 p.Ala198Thr Uncertain significance ★★ ⚠ same type
GRHL2 p.Ala28Gly Uncertain significance ★★ ⚠ same type
GRHL2 p.Ala327Val Uncertain significance ★★ ⚠ same type

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-ser613arg (accessed [today's date]).

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