Is GABRE p.Pro40Leu (c.119C>T) pathogenic?

GABRE p.Pro40Leu (c.119C>T) is classified Uncertain significance in GABRE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: likely benign (0.1265); Very rare (popmax 0.00827%, nfe).

How common is GABRE p.Pro40Leu (c.119C>T) in the general population?

GABRE p.Pro40Leu (c.119C>T) is very rare (popmax 0.00827%, nfe) (gnomAD).

What do computational predictors say about GABRE p.Pro40Leu (c.119C>T)?

AlphaMissense predicts likely benign (score 0.1265) — an in-silico prediction, not a clinical call.

GABRE p.Pro40Leu

c.119C>T · rs201820607 · VCV2463132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1265 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00827%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1265	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -6.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 20 kb · p 0.65 · regional, not allelic
Overall
CADD	18.05	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 0.00827% European (non-Finnish) · 74/895,277 alleles

Filtering AF 0.00673% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00617%

Overall 0.00653% 79/1,209,998 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00827%	12,098
Remaining individualsnot grpmax-eligible	0.0042%	23,786
African / African-American	0.00349%	28,620
South Asian	0.00176%	56,765

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.Pro40Leu
Coding: c.119C>T
MANE Select: NM_004961
dbSNP: rs201820607
Type: single nucleotide variant
Location: chrX:151970340 (GRCh38)
Structure: AlphaFold pLDDT 73.13
Residue 40: the 'disordered' region

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-pro40leu (accessed [today's date]).

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