Is GPATCH2 p.Tyr199His (c.595T>C) pathogenic?

GPATCH2 p.Tyr199His (c.595T>C) is classified Uncertain significance in GPATCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.1049); Ultra-rare (popmax 0.0307%, afr).

How common is GPATCH2 p.Tyr199His (c.595T>C) in the general population?

GPATCH2 p.Tyr199His (c.595T>C) is ultra-rare (popmax 0.0307%, afr) (gnomAD).

What do computational predictors say about GPATCH2 p.Tyr199His (c.595T>C)?

AlphaMissense predicts likely benign (score 0.1049) — an in-silico prediction, not a clinical call.

GPATCH2 p.Tyr199His

c.595T>C · VCV4827909

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1049 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1049	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.3	GERP 1.3, phastCons 0.45
Regional constraint	o/e 0.96	unconstrained · MANE · 200 kb · p 0.29 · regional, not allelic
Overall
CADD	18.61	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 0.0307% African / African-American · 23/74,880 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.00248% 40/1,613,870 alleles · ultra-rare exomes 28/1,461,818 · genomes 12/152,052 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0307%	3,256
Admixed American	0.00333%	29,986
European (non-Finnish)	0.00127%	78,666

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.Tyr199His
Coding: c.595T>C
MANE Select: NM_018040
Type: single nucleotide variant
Location: chr1:217619961 (GRCh38)
Gene constraint: LOEUF 1.233 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.60

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-tyr199his (accessed [today's date]).

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