Is GRK5 p.Gln179Pro (c.536A>C) pathogenic?

GRK5 p.Gln179Pro (c.536A>C) is classified Uncertain significance in GRK5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-07). AlphaMissense: likely pathogenic (0.9539); Very rare (popmax 0.000254%, nfe).

How common is GRK5 p.Gln179Pro (c.536A>C) in the general population?

GRK5 p.Gln179Pro (c.536A>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about GRK5 p.Gln179Pro (c.536A>C)?

AlphaMissense predicts likely pathogenic (score 0.9539) — an in-silico prediction, not a clinical call.

GRK5 p.Gln179Pro

c.536A>C · VCV3522825

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9539 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9539	likely pathogenic
REVEL	0.467	indeterminate
SaProt	LLR -17.08	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 11	GERP 0.45, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 247 kb · p 4.3e-09 · regional, not allelic
Overall
CADD	27.5	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 0.000254% European (non-Finnish) · 3/1,179,634 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,294 alleles · very rare

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: GRK5
Protein: p.Gln179Pro
Coding: c.536A>C
MANE Select: NM_005308
Type: single nucleotide variant
Location: chr10:119430377 (GRCh38)
Gene constraint: LOEUF 0.604 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 23 PDB
Residue 179: the 'n-terminal' region

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

Similar variants

GRK5 p.Gln179His Uncertain significance ★ ⚠ same residue
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

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-gln179pro (accessed [today's date]).

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