Is AAK1 p.Leu656Phe (c.1966C>T) pathogenic?

AAK1 p.Leu656Phe (c.1966C>T) is classified Uncertain significance in AAK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely pathogenic (0.8681); Absent from gnomAD v4.1.

How common is AAK1 p.Leu656Phe (c.1966C>T) in the general population?

AAK1 p.Leu656Phe (c.1966C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AAK1 p.Leu656Phe (c.1966C>T)?

AlphaMissense predicts likely pathogenic (score 0.8681) — an in-silico prediction, not a clinical call.

AAK1 p.Leu656Phe

c.1966C>T · VCV3920185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8681 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8681	likely pathogenic
REVEL	0.171	moderately benign-leaning
SaProt	LLR -12.06	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 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 8,860 bp · p 1.3e-05 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AAK1
Protein: p.Leu656Phe
Coding: c.1966C>T
MANE Select: NM_014911
Type: single nucleotide variant
Location: chr2:69509271 (GRCh38)
Gene constraint: LOEUF 0.406 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.43 · 8 PDB

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-leu656phe (accessed [today's date]).

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