Is GRK5 p.Val349Phe (c.1045G>T) pathogenic?

GRK5 p.Val349Phe (c.1045G>T) is classified Uncertain significance in GRK5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-04). AlphaMissense: likely pathogenic (0.9222); Absent from gnomAD v4.1.

How common is GRK5 p.Val349Phe (c.1045G>T) in the general population?

GRK5 p.Val349Phe (c.1045G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GRK5 p.Val349Phe (c.1045G>T)?

AlphaMissense predicts likely pathogenic (score 0.9222) — an in-silico prediction, not a clinical call.

GRK5 p.Val349Phe

c.1045G>T · VCV3855895

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9222 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9222	likely pathogenic
REVEL	0.494	indeterminate
SaProt	LLR -14.20	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 247 kb · p 4.3e-09 · regional, not allelic
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GRK5
Protein: p.Val349Phe
Coding: c.1045G>T
MANE Select: NM_005308
Type: single nucleotide variant
Location: chr10:119442076 (GRCh38)
Gene constraint: LOEUF 0.604 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 23 PDB
Residue 349: the protein kinase domain

Full GRK5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRK5 c.440+10G>A Likely benign ★★ same type
GRK5 c.440+9C>T Benign ★★ same type
GRK5 p.Ala119Val Benign ★★ same type
GRK5 p.Leu141Ile Benign ★★ same type
GRK5 p.Phe448Leu Benign ★★ same type
GRK5 p.Ala471Thr Uncertain significance ★ ⚠ same type
GRK5 p.Arg169His Uncertain significance ★ ⚠ same type
GRK5 p.Arg206Trp 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/grk5-p-val349phe (accessed [today's date]).

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