Is GABRR3 p.Phe153Leu (c.459C>A) pathogenic?

GABRR3 p.Phe153Leu (c.459C>A) is classified Uncertain significance in GABRR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely pathogenic (0.9307); Very rare (popmax 0.00017%, nfe).

How common is GABRR3 p.Phe153Leu (c.459C>A) in the general population?

GABRR3 p.Phe153Leu (c.459C>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about GABRR3 p.Phe153Leu (c.459C>A)?

AlphaMissense predicts likely pathogenic (score 0.9307) — an in-silico prediction, not a clinical call.

GABRR3 p.Phe153Leu

c.459C>A · VCV4261216

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9307 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.9307	likely pathogenic · top 4% in GABRR3
SaProt	LLR -9.53	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.30	acceptor loss, 6 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 3.4	GERP -0.002, phastCons 1
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; SaProt is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,862 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,966 alleles · very rare exomes 2/1,461,664 · genomes 0/152,302 · 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: GABRR3
Protein: p.Phe153Leu
Coding: c.459C>A
MANE Select: NM_001105580
Type: single nucleotide variant
Location: chr3:98012415 (GRCh38)
Gene constraint: LOEUF 0.861 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.27

Full GABRR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GABRR3 p.Ala241Glu Uncertain significance ★ same type
GABRR3 p.Ala246Ser Uncertain significance ★ ⚠ same type
GABRR3 p.Ala319Thr Uncertain significance ★ ⚠ same type
GABRR3 p.Ala4Asp Uncertain significance ★ ⚠ same type
GABRR3 p.Ala73Ser Uncertain significance ★ ⚠ same type
GABRR3 p.Arg111Thr Uncertain significance ★ ⚠ same type
GABRR3 p.Arg118Lys Uncertain significance ★ same type
GABRR3 p.Arg165Cys 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/gabrr3-p-phe153leu (accessed [today's date]).

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