Is HAP1 p.Val369Ala (c.1106T>C) pathogenic?

HAP1 p.Val369Ala (c.1106T>C) is classified Benign in HAP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-05-21). AlphaMissense: likely pathogenic (0.6113); Common (popmax 5.78%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about HAP1 p.Val369Ala (c.1106T>C)?

AlphaMissense predicts likely pathogenic (score 0.6113) — an in-silico prediction, not a clinical call.

HAP1 p.Val369Ala

Q: How common is HAP1 p.Val369Ala (c.1106T>C) in the general population?

HAP1 p.Val369Ala (c.1106T>C) is common (popmax 5.78%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1106T>C · rs147253461 · VCV787453

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6113 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.78%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6113	likely pathogenic · top 7% in HAP1
REVEL	0.086	moderately benign-leaning
SaProt	LLR -4.91	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	GERP -2.3, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 9,930 bp · p 0.16 · regional, not allelic
Overall
CADD	19.19	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.78% African / African-American · 4,332/75,006 alleles

Filtering AF 5.63% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.57%

Overall 0.319% 5,153/1,613,478 alleles · common exomes 2,643/1,461,256 · genomes 2,510/152,222 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.78%	17
Middle Eastern	0.759%	132
Admixed American	0.452%	221
Remaining individualsnot grpmax-eligible	0.45%	222
South Asian	0.0209%	4,794
European (non-Finnish)	0.017%	5,871
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,802
Finnishnot grpmax-eligible	0.00158%	63,458

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.Val369Ala
Coding: c.1106T>C
MANE Select: NM_177977
dbSNP: rs147253461
Type: single nucleotide variant
Location: chr17:41728295 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.28
Residue 369: the hap1 n-terminal domain

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

Similar variants

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
HAP1 p.Thr66Ala Likely 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-val369ala (accessed [today's date]).

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