Is GRK1 p.Phe528Ser (c.1583T>C) pathogenic?

GRK1 p.Phe528Ser (c.1583T>C) is classified Uncertain significance in GRK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-22). AlphaMissense: likely pathogenic (0.8886); Very rare (popmax 0.000174%, nfe).

How common is GRK1 p.Phe528Ser (c.1583T>C) in the general population?

GRK1 p.Phe528Ser (c.1583T>C) is very rare (popmax 0.000174%, nfe) (gnomAD).

What do computational predictors say about GRK1 p.Phe528Ser (c.1583T>C)?

AlphaMissense predicts likely pathogenic (score 0.8886) — an in-silico prediction, not a clinical call.

GRK1 p.Phe528Ser

c.1583T>C · VCV4920783

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8886 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000174%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8886	likely pathogenic
REVEL	0.26	benign-leaning
SaProt	LLR -14.43	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.3, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 68 kb · p 0.22 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000174% European (non-Finnish) · 2/1,146,848 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00013% 2/1,537,076 alleles · very rare exomes 2/1,384,764 · genomes 0/152,312 · 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: GRK1
Protein: p.Phe528Ser
Coding: c.1583T>C
MANE Select: NM_002929
Type: single nucleotide variant
Location: chr13:113735254 (GRCh38)
Gene constraint: LOEUF 1.103 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.04 · 1 PDB
Residue 528: the 'c-terminal' region

Full GRK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRK1 p.Phe528= Likely benign ★ same residue
GRK1 c.1194+1G>A Pathogenic/Likely pathogenic ★★ same type
GRK1 p.Val380Asp Pathogenic/Likely pathogenic ★★ same type
GRK1 p.Ala18Thr Uncertain significance ★★ ⚠ same type
GRK1 p.Ala394Val Uncertain significance ★★ ⚠ same type
GRK1 p.Arg31Trp Uncertain significance ★★ same type
GRK1 p.Arg51Cys Uncertain significance ★★ ⚠ same type
GRK1 p.Asp262His 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/grk1-p-phe528ser (accessed [today's date]).

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