Is GPATCH2 p.Gly269Ala (c.806G>C) pathogenic?

GPATCH2 p.Gly269Ala (c.806G>C) is classified Uncertain significance in GPATCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-28). AlphaMissense: likely pathogenic (0.7562); Ultra-rare (popmax 0.041%, sas).

How common is GPATCH2 p.Gly269Ala (c.806G>C) in the general population?

GPATCH2 p.Gly269Ala (c.806G>C) is ultra-rare (popmax 0.041%, sas) (gnomAD).

What do computational predictors say about GPATCH2 p.Gly269Ala (c.806G>C)?

AlphaMissense predicts likely pathogenic (score 0.7562) — an in-silico prediction, not a clinical call.

GPATCH2 p.Gly269Ala

c.806G>C · VCV4672849

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7562 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.041%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7562	likely pathogenic
REVEL	0.441	indeterminate
SaProt	LLR -6.53	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 200 kb · p 0.29 · regional, not allelic
Overall
CADD	25.9	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 0.041% South Asian · 37/90,350 alleles

Filtering AF 0.0305% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0269%

Overall 0.00971% 154/1,586,084 alleles · ultra-rare exomes 144/1,434,012 · genomes 10/152,072 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0625%	1,600
South Asiangrpmax	0.041%	2,442
Remaining individualsnot grpmax-eligible	0.0065%	15,386
European (non-Finnish)	0.00632%	15,821

Finnish 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: GPATCH2
Protein: p.Gly269Ala
Coding: c.806G>C
MANE Select: NM_018040
Type: single nucleotide variant
Location: chr1:217614170 (GRCh38)
Gene constraint: LOEUF 1.233 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.60
Residue 269: the 'disordered' region

Full GPATCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GPATCH2 p.Ala396Val Uncertain significance ★ ⚠ same type
GPATCH2 p.Arg126His Uncertain significance ★ ⚠ same type
GPATCH2 p.Arg137Gln Uncertain significance ★ ⚠ same type
GPATCH2 p.Arg159Cys Uncertain significance ★ ⚠ same type
GPATCH2 p.Arg212Ile Uncertain significance ★ ⚠ same type
GPATCH2 p.Arg218Lys Uncertain significance ★ ⚠ same type
GPATCH2 p.Arg347Cys Uncertain significance ★ ⚠ same type
GPATCH2 p.Arg410Gln 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/gpatch2-p-gly269ala (accessed [today's date]).

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