Is GABRE p.Cys209Phe (c.626G>T) pathogenic?

GABRE p.Cys209Phe (c.626G>T) is classified Uncertain significance in GABRE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely pathogenic (0.9576); Ultra-rare (popmax 0.0654%, eas).

How common is GABRE p.Cys209Phe (c.626G>T) in the general population?

GABRE p.Cys209Phe (c.626G>T) is ultra-rare (popmax 0.0654%, eas) (gnomAD).

What do computational predictors say about GABRE p.Cys209Phe (c.626G>T)?

AlphaMissense predicts likely pathogenic (score 0.9576) — an in-silico prediction, not a clinical call.

GABRE p.Cys209Phe

c.626G>T · VCV4027737

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9576 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0654%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9576	likely pathogenic · top 5% in GABRE
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -15.12	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 4.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 20 kb · p 0.65 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0654% East Asian · 22/33,651 alleles

Filtering AF 0.0442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0373%

Overall 0.00199% 24/1,204,356 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0654%	1,530
Remaining individualsnot grpmax-eligible	0.00211%	47,446
European (non-Finnish)	0.000112%	891,194

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: GABRE
Protein: p.Cys209Phe
Coding: c.626G>T
MANE Select: NM_004961
Type: single nucleotide variant
Location: chrX:151961303 (GRCh38)
Structure: AlphaFold pLDDT 73.13
Residue 209: a disulfide bond

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

Similar variants

GABRE p.Arg176His Uncertain significance ★★ ⚠ same type
GABRE p.Asn134= Likely benign ★★ same type
GABRE p.Glu435Asp Benign ★★ same type
GABRE p.Gly62= Benign ★★ same type
GABRE p.Leu323= Benign ★★ same type
GABRE p.Ser102Ala Benign ★★ same type
GABRE p.Ala193Gly Uncertain significance ★ ⚠ same type
GABRE p.Ala193Thr 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/gabre-p-cys209phe (accessed [today's date]).

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