Is HAP1 p.Arg8Trp (c.22C>T) pathogenic?

HAP1 p.Arg8Trp (c.22C>T) is classified Likely benign in HAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-04). AlphaMissense: likely benign (0.1505); Rare (popmax 0.872%, afr).

How common is HAP1 p.Arg8Trp (c.22C>T) in the general population?

HAP1 p.Arg8Trp (c.22C>T) is rare (popmax 0.872%, afr) (gnomAD).

What do computational predictors say about HAP1 p.Arg8Trp (c.22C>T)?

AlphaMissense predicts likely benign (score 0.1505) — an in-silico prediction, not a clinical call.

HAP1 p.Arg8Trp

c.22C>T · rs201166499 · VCV783782

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1505 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.872%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1505	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -8.03	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 0.021	GERP -2.7
Regional constraint	o/e 1.05	unconstrained · MANE · 9,930 bp · p 0.16 · regional, not allelic
Overall
CADD	16.7	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 0.872% African / African-American · 643/73,748 alleles

Filtering AF 0.816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.794%

Overall 0.0662% 1,027/1,551,990 alleles · rare exomes 657/1,399,704 · genomes 370/152,286 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.872%	115
Remaining individualsnot grpmax-eligible	0.0733%	1,364
South Asian	0.043%	2,328
Middle Eastern	0.0361%	2,772
Admixed American	0.0295%	3,389
European (non-Finnish)	0.0242%	4,137
East Asian	0.0115%	8,665
Ashkenazi Jewishnot grpmax-eligible	0.0036%	27,814
Finnishnot grpmax-eligible	0.002%	50,100

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.Arg8Trp
Coding: c.22C>T
MANE Select: NM_177977
dbSNP: rs201166499
Type: single nucleotide variant
Location: chr17:41734613 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.28
Residue 8: the 'disordered' region

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

Similar variants

HAP1 p.Arg8Gly 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-arg8trp (accessed [today's date]).

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