Is HYPK p.Ala115Val (c.344C>T) pathogenic?

HYPK p.Ala115Val (c.344C>T) is classified Uncertain significance in HYPK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-16). AlphaMissense: likely pathogenic (0.9598); Very rare (popmax 0.00133%, afr).

How common is HYPK p.Ala115Val (c.344C>T) in the general population?

HYPK p.Ala115Val (c.344C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about HYPK p.Ala115Val (c.344C>T)?

AlphaMissense predicts likely pathogenic (score 0.9598) — an in-silico prediction, not a clinical call.

HYPK p.Ala115Val

c.344C>T · VCV4036992

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9598 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Computational evidence

Protein change
AlphaMissense	0.9598	likely pathogenic
REVEL	0.609	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	Δ0.57	donor gain · deltas
Pangolin	Δ0.78	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 0.79, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,043 bp · p 0.56 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A123V vs ClinVar A115V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,930 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000743% 12/1,614,020 alleles · very rare exomes 9/1,461,812 · genomes 3/152,208 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,930
European (non-Finnish)	0.000932%	107,270

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.Ala115Val
Coding: c.344C>T
MANE Select: NM_016400
Type: single nucleotide variant
Location: chr15:43801784 (GRCh38)
Gene constraint: LOEUF 1.059 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.87 · 3 PDB

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.Ala118Thr Uncertain significance ★ ⚠ same type
HYPK p.Ala118Val Uncertain significance ★ ⚠ same type
HYPK p.Ala99Thr Uncertain significance ★ ⚠ same type
HYPK p.Arg103His 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-ala115val (accessed [today's date]).

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