Is HK2 p.Pro288Ser (c.862C>T) pathogenic?

HK2 p.Pro288Ser (c.862C>T) is classified Uncertain significance in HK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-11). AlphaMissense: likely pathogenic (0.6461); Ultra-rare (popmax 0.0827%, mid).

How common is HK2 p.Pro288Ser (c.862C>T) in the general population?

HK2 p.Pro288Ser (c.862C>T) is ultra-rare (popmax 0.0827%, mid) (gnomAD).

What do computational predictors say about HK2 p.Pro288Ser (c.862C>T)?

AlphaMissense predicts likely pathogenic (score 0.6461) — an in-silico prediction, not a clinical call.

HK2 p.Pro288Ser

c.862C>T · rs531793433 · VCV2343755

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6461 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0827%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6461	likely pathogenic · top 10% in HK2
REVEL	0.343	indeterminate
SaProt	LLR -10.46	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Overall
CADD	24.3	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 0.0827% Middle Eastern · 5/6,048 alleles

Filtering AF 0.0326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0211%

Overall 0.00604% 97/1,605,364 alleles · ultra-rare exomes 90/1,453,112 · genomes 7/152,252 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0827%	1,210
Ashkenazi Jewishnot grpmax-eligible	0.0272%	3,680
Remaining individualsnot grpmax-eligible	0.0145%	6,914
Admixed American	0.0085%	11,763
African / African-American	0.00668%	14,967
European (non-Finnish)	0.00553%	18,079

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.Pro288Ser
Coding: c.862C>T
MANE Select: NM_000189
dbSNP: rs531793433
Type: single nucleotide variant
Location: chr2:74874436 (GRCh38)
Structure: AlphaFold pLDDT 82.81
Residue 288: the 'sufficient for interaction with microtubules' region

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

Similar variants

HK2 p.Pro288Leu Uncertain significance ★ ⚠ same residue
HK2 p.Arg44Cys Uncertain significance ★★ ⚠ same type
HK2 p.Tyr515= Benign ★★ same type
HOOK2 c.519+7G>T Benign ★★ same type
HOOK2 p.Glu657Lys Likely benign ★★ ⚠ same type
HOOK2 p.Val445Leu Benign ★★ same type
HK2 p.Ala352Thr Uncertain significance ★ ⚠ same type
HK2 p.Ala383Thr 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/hk2-p-pro288ser (accessed [today's date]).

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