Is HYPK p.Leu89= (c.267A>G) pathogenic?

HYPK p.Leu89= (c.267A>G) is classified Likely benign in HYPK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). Ultra-rare (popmax 0.016%, afr).

How common is HYPK p.Leu89= (c.267A>G) in the general population?

HYPK p.Leu89= (c.267A>G) is ultra-rare (popmax 0.016%, afr) (gnomAD).

HYPK p.Leu89=

c.267A>G · VCV4273137

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.086	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -1.4, phastCons 1
Overall
CADD	11.46	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% African / African-American · 12/74,918 alleles

Filtering AF 0.00921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.000744% 12/1,613,764 alleles · ultra-rare exomes 4/1,461,554 · genomes 8/152,210 · joint denominator

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: HYPK
Protein: p.Leu89=
Coding: c.267A>G
MANE Select: NM_016400
Type: single nucleotide variant
Location: chr15:43801566 (GRCh38)
Gene constraint: LOEUF 1.059 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.87 · 3 PDB
Residue 89: an α-helix; the 'required for association with the naa10-naa15 complex' region

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

Similar variants

HYPK p.Glu12= Benign ★★ same type
HYPK c.-11G>A Uncertain significance ★ ⚠ same type
HYPK c.-17G>A Uncertain significance ★ ⚠ same type
HYPK c.-18C>T Uncertain significance ★ ⚠ same type
HYPK p.Ala115Val Uncertain significance ★ same type
HYPK p.Ala118Thr Uncertain significance ★ ⚠ same type
HYPK p.Ala118Val Uncertain significance ★ ⚠ same type
HYPK p.Ala99Thr 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/hypk-p-leu89 (accessed [today's date]).

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