Is GAK p.Arg464Ser (c.1392G>T) pathogenic?

GAK p.Arg464Ser (c.1392G>T) is classified Uncertain significance in GAK (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: likely pathogenic (0.9023); Ultra-rare (popmax 0.0417%, sas).

How common is GAK p.Arg464Ser (c.1392G>T) in the general population?

GAK p.Arg464Ser (c.1392G>T) is ultra-rare (popmax 0.0417%, sas) (gnomAD).

What do computational predictors say about GAK p.Arg464Ser (c.1392G>T)?

AlphaMissense predicts likely pathogenic (score 0.9023) — an in-silico prediction, not a clinical call.

GAK p.Arg464Ser

c.1392G>T · rs144499981 · VCV2362992

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9023 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0417%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9023	likely pathogenic
REVEL	0.477	indeterminate
SaProt	LLR -10.38	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.71	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.38	GERP -0.75, phastCons 0.069
Regional constraint	o/e 0.88	unconstrained · MANE · 61 kb · p 0.00014 · regional, not allelic
Overall
CADD	20.2	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 0.0417% South Asian · 38/91,066 alleles

Filtering AF 0.0312% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0276%

Overall 0.0167% 270/1,613,354 alleles · ultra-rare exomes 247/1,461,006 · genomes 23/152,348 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.368%	271
South Asiangrpmax	0.0417%	2,396
Admixed American	0.0267%	3,750
Remaining individualsnot grpmax-eligible	0.0256%	3,905
African / African-American	0.0147%	6,824
East Asian	0.0134%	7,479
European (non-Finnish)	0.00627%	15,945

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: GAK
Protein: p.Arg464Ser
Coding: c.1392G>T
MANE Select: NM_005255
dbSNP: rs144499981
Type: single nucleotide variant
Location: chr4:883327 (GRCh38)
Gene constraint: LOEUF 0.687 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.32 · 7 PDB
Residue 464: the phosphatase tensin-type domain

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

Similar variants

GAK p.Arg464Gly Uncertain significance ★ ⚠ same residue
GAK p.Ala1255= Likely benign ★★ same type
GAK p.Asp1297= Benign ★★ same type
GAK p.Glu1020= Benign/Likely benign ★★ same type
GAK p.Glu816Lys Benign ★★ same type
GAK p.His1287= Benign ★★ same type
GAK p.Lys1265Arg Benign ★★ same type
GAK p.Pro1139Arg Benign ★★ ⚠ 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/gak-p-arg464ser (accessed [today's date]).

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