Is HK2 p.Ala424= (c.1272C>G) pathogenic?

HK2 p.Ala424= (c.1272C>G) is classified Likely benign in HK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-22). Very rare (popmax 0.00153%, nfe); Associated with HK2-related disorder.

What condition is associated with HK2 p.Ala424= (c.1272C>G)?

HK2 p.Ala424= (c.1272C>G) is associated with HK2-related disorder (ClinVar).

How common is HK2 p.Ala424= (c.1272C>G) in the general population?

HK2 p.Ala424= (c.1272C>G) is very rare (popmax 0.00153%, nfe) (gnomAD).

HK2 p.Ala424=

c.1272C>G · rs375820063 · VCV3052617

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Conditions

HK2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.25	GERP -1, phastCons 0.98
Overall
CADD	6.256	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,180,046 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00118% 19/1,613,998 alleles · very rare exomes 17/1,461,780 · genomes 2/152,218 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00153%	65,558
African / African-American	0.00133%	74,938

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: HK2
Protein: p.Ala424=
Coding: c.1272C>G
MANE Select: NM_000189
dbSNP: rs375820063
Type: single nucleotide variant
Location: chr2:74880271 (GRCh38)
Structure: AlphaFold pLDDT 82.81
Residue 424: the 'sufficient for interaction with microtubules' region

Full HK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

HK2-related disorder

Similar variants

HOOK2 p.Ala424Thr Uncertain significance ★ ⚠ same residue
HK2 c.591+10G>A Benign same condition
HK2 p.Ala113= Likely benign same condition
HK2 p.Ala387= Likely benign same condition
HK2 p.Ala387Ser Benign same condition
HK2 p.Ala831= Benign same condition
HK2 p.Arg844Lys Benign same condition
HK2 p.Asn692= Benign same condition

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/hk2-p-ala424 (accessed [today's date]).

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