Is AAK1 p.Arg141His (c.422G>A) pathogenic?

AAK1 p.Arg141His (c.422G>A) is classified Uncertain significance in AAK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). AlphaMissense: ambiguous (0.4922); Very rare (popmax 0.005%, amr).

How common is AAK1 p.Arg141His (c.422G>A) in the general population?

AAK1 p.Arg141His (c.422G>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about AAK1 p.Arg141His (c.422G>A)?

AlphaMissense predicts ambiguous (score 0.4922) — an in-silico prediction, not a clinical call.

AAK1 p.Arg141His

c.422G>A · VCV3808406

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4922 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Computational evidence

Protein change
AlphaMissense	0.4922	ambiguous
REVEL	0.39	indeterminate
SaProt	LLR -9.82	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 122 kb · p 4.9e-15 · regional, not allelic
Overall
CADD	31.0	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 0.005% Admixed American · 3/59,998 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00149% 24/1,613,752 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00801%	12,492
Admixed Americangrpmax	0.005%	19,999
East Asian	0.00223%	44,898
South Asian	0.0022%	45,539
African / African-American	0.00134%	74,906
European (non-Finnish)	0.00102%	98,323

Remaining individuals 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: AAK1
Protein: p.Arg141His
Coding: c.422G>A
MANE Select: NM_014911
Type: single nucleotide variant
Location: chr2:69542635 (GRCh38)
Gene constraint: LOEUF 0.406 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.43 · 8 PDB
Residue 141: the protein kinase domain

Full AAK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AAK1 p.Gly105= Likely benign ★★ same type
AAK1 p.Leu719= Benign ★★ same type
AAK1 p.Thr694Met Benign ★★ ⚠ same type
AAK1 c.1777-2A>T Uncertain significance ★ same type
AAK1 p.Ala344Thr Uncertain significance ★ ⚠ same type
AAK1 p.Ala351Thr Uncertain significance ★ ⚠ same type
AAK1 p.Ala387Val Uncertain significance ★ ⚠ same type
AAK1 p.Ala455Ser 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/aak1-p-arg141his (accessed [today's date]).

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