Is HAP1 p.Val509Leu (c.1525G>T) pathogenic?

HAP1 p.Val509Leu (c.1525G>T) is classified Uncertain significance in HAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-13). AlphaMissense: likely benign (0.1569); Ultra-rare (popmax 0.068%, afr).

How common is HAP1 p.Val509Leu (c.1525G>T) in the general population?

HAP1 p.Val509Leu (c.1525G>T) is ultra-rare (popmax 0.068%, afr) (gnomAD).

What do computational predictors say about HAP1 p.Val509Leu (c.1525G>T)?

AlphaMissense predicts likely benign (score 0.1569) — an in-silico prediction, not a clinical call.

HAP1 p.Val509Leu

c.1525G>T · VCV3523904

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1569 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.068%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1569	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.17, phastCons 0.87
Regional constraint	o/e 1.05	unconstrained · MANE · 9,930 bp · p 0.16 · regional, not allelic
Overall
CADD	16.34	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V561L vs ClinVar V509L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.068% African / African-American · 51/75,012 alleles

Filtering AF 0.0531% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0478%

Overall 0.00323% 52/1,612,378 alleles · ultra-rare exomes 15/1,460,116 · genomes 37/152,262 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.068%	1,471
Remaining individualsnot grpmax-eligible	0.0016%	62,442

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: HAP1
Protein: p.Val509Leu
Coding: c.1525G>T
MANE Select: NM_177977
Type: single nucleotide variant
Location: chr17:41725036 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.28

Full HAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HAP1 p.Val509Met Uncertain significance ★ ⚠ same residue
HAP1 p.Arg106Pro Uncertain significance ★★ ⚠ same type
HAP1 p.Cys25Tyr Benign ★★ same type
HAP1 p.Gly604Arg Benign ★★ same type
HAP1 p.Ile496Val Benign ★★ same type
HAP1 p.Leu348= Benign ★★ same type
HAP1 p.Ser616Ter Benign ★★ same type
HAP1 p.Thr441Met Benign ★★ 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/hap1-p-val509leu (accessed [today's date]).

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