Is HK2 p.Pro736= (c.2208C>G) pathogenic?

HK2 p.Pro736= (c.2208C>G) is classified Benign in HK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-17). Common (popmax 72.9%, mid) — too common for a highly-penetrant pathogenic allele; Associated with HK2-related disorder.

What condition is associated with HK2 p.Pro736= (c.2208C>G)?

HK2 p.Pro736= (c.2208C>G) is associated with HK2-related disorder (ClinVar).

HK2 p.Pro736=

Q: How common is HK2 p.Pro736= (c.2208C>G) in the general population?

HK2 p.Pro736= (c.2208C>G) is common (popmax 72.9%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2208C>G · rs2229627 · VCV3060889

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 72.9%, mid) — too common for a highly-penetrant pathogenic allele

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 -9.2	GERP -4.1
Overall
CADD	0.164	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 72.9% Middle Eastern · 4,417/6,062 alleles

Filtering AF 71.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 70.3%

Overall 58.6% 946,102/1,613,306 alleles · common exomes 862,985/1,461,722 · genomes 83,117/151,584 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	72.9%	1
South Asian	64.4%	2
Ashkenazi Jewishnot grpmax-eligible	61.2%	2
Finnishnot grpmax-eligible	61.2%	2
European (non-Finnish)	59.9%	2
Remaining individualsnot grpmax-eligible	58.4%	2
East Asian	49.8%	2
Amishnot grpmax-eligible	46.8%	2
Admixed American	45.6%	2
African / African-American	44%	2

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.Pro736=
Coding: c.2208C>G
MANE Select: NM_000189
dbSNP: rs2229627
Type: single nucleotide variant
Location: chr2:74886662 (GRCh38)
Structure: AlphaFold pLDDT 82.81

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

Disease context

HK2-related disorder

Similar variants

HK2 p.Pro736Leu Likely benign ⚠ 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.Ala424= Likely benign same condition
HK2 p.Ala831= Benign same condition
HK2 p.Arg844Lys 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-pro736 (accessed [today's date]).

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