Is GRK4 p.Leu331Phe (c.991C>T) pathogenic?

GRK4 p.Leu331Phe (c.991C>T) is classified Uncertain significance in GRK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: ambiguous (0.4332); Ultra-rare (popmax 0.0614%, afr).

How common is GRK4 p.Leu331Phe (c.991C>T) in the general population?

GRK4 p.Leu331Phe (c.991C>T) is ultra-rare (popmax 0.0614%, afr) (gnomAD).

What do computational predictors say about GRK4 p.Leu331Phe (c.991C>T)?

AlphaMissense predicts ambiguous (score 0.4332) — an in-silico prediction, not a clinical call.

GRK4 p.Leu331Phe

c.991C>T · rs200471975 · VCV2509087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4332 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0614%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4332	ambiguous
REVEL	0.224	benign-leaning
SaProt	LLR -5.32	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 77 kb · p 0.28 · regional, not allelic
Overall
CADD	24.7	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 0.0614% African / African-American · 46/74,866 alleles

Filtering AF 0.0472% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0423%

Overall 0.00353% 57/1,613,940 alleles · ultra-rare exomes 20/1,461,872 · genomes 37/152,068 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0614%	1,628
Admixed American	0.00834%	11,997
Remaining individualsnot grpmax-eligible	0.008%	12,498
European (non-Finnish)	8.47e-05%	1,180,018

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: GRK4
Protein: p.Leu331Phe
Coding: c.991C>T
MANE Select: NM_182982
dbSNP: rs200471975
Type: single nucleotide variant
Location: chr4:3027932 (GRCh38)
Gene constraint: LOEUF 1.262 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.80 · 1 PDB
Residue 331: the protein kinase domain

Full GRK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRK4 p.Gln173Ter Benign ★★ same type
GRK4 p.Ala203Thr Uncertain significance ★ ⚠ same type
GRK4 p.Ala259Gly Uncertain significance ★ ⚠ same type
GRK4 p.Ala334Gly Uncertain significance ★ same type
GRK4 p.Ala86Thr Uncertain significance ★ ⚠ same type
GRK4 p.Arg108Lys Uncertain significance ★ ⚠ same type
GRK4 p.Arg207Gln Uncertain significance ★ ⚠ same type
GRK4 p.Arg226Lys 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/grk4-p-leu331phe (accessed [today's date]).

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