Is HAP1 p.Ala505Val (c.1514C>T) pathogenic?

HAP1 p.Ala505Val (c.1514C>T) is classified Benign in HAP1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-02-28). AlphaMissense: likely benign (0.1114); Common (popmax 9.06%, afr) — too common for a highly-penetrant pathogenic allele; Associated with HAP1-related disorder.

What condition is associated with HAP1 p.Ala505Val (c.1514C>T)?

HAP1 p.Ala505Val (c.1514C>T) is associated with HAP1-related disorder (ClinVar).

What do computational predictors say about HAP1 p.Ala505Val (c.1514C>T)?

AlphaMissense predicts likely benign (score 0.1114) — an in-silico prediction, not a clinical call.

HAP1 p.Ala505Val

Q: How common is HAP1 p.Ala505Val (c.1514C>T) in the general population?

HAP1 p.Ala505Val (c.1514C>T) is common (popmax 9.06%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1514C>T · rs34853043 · VCV3037352

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1114 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.06%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HAP1-related disorder

Computational evidence

Protein change
AlphaMissense	0.1114	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -6.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.5	GERP -1.9
Regional constraint	o/e 1.05	unconstrained · MANE · 9,930 bp · p 0.16 · regional, not allelic
Overall
CADD	0.658	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A557V vs ClinVar A505V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.06% African / African-American · 6,786/74,902 alleles

Filtering AF 8.88% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.81%

Overall 1.36% 21,898/1,612,234 alleles · common exomes 16,952/1,460,160 · genomes 4,946/152,074 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.06%	11
Ashkenazi Jewishnot grpmax-eligible	4.58%	22
Middle Eastern	1.8%	56
Remaining individualsnot grpmax-eligible	1.6%	63
Admixed American	1.37%	73
Amishnot grpmax-eligible	0.989%	101
European (non-Finnish)	0.965%	104
Finnishnot grpmax-eligible	0.394%	254
South Asian	0.208%	481
East Asian	0.0112%	8,966

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.Ala505Val
Coding: c.1514C>T
MANE Select: NM_177977
dbSNP: rs34853043
Type: single nucleotide variant
Location: chr17:41725047 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.28
Residue 557 UniProt numbering: a UniProt-annotated variant site (in)

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

Disease context

HAP1-related disorder

Similar variants

HAP1 c.1201-4C>T Likely benign same condition
HAP1 c.1201-7C>T Likely benign same condition
HAP1 c.470-7C>G Likely benign same condition
HAP1 p.Ala21= Likely benign same condition
HAP1 p.Arg116Trp Likely benign same condition
HAP1 p.Asp339Asn Likely benign same condition
HAP1 p.Leu408Phe Benign ⚠ same condition
HAP1 p.Pro187His Likely 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/hap1-p-ala505val (accessed [today's date]).

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