Is HAP1 p.Arg116Trp (c.346C>T) pathogenic?

HAP1 p.Arg116Trp (c.346C>T) is classified Likely benign in HAP1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-02-10). AlphaMissense: likely benign (0.2065); Rare (popmax 0.556%, nfe); Associated with HAP1-related disorder.

What condition is associated with HAP1 p.Arg116Trp (c.346C>T)?

HAP1 p.Arg116Trp (c.346C>T) is associated with HAP1-related disorder (ClinVar).

How common is HAP1 p.Arg116Trp (c.346C>T) in the general population?

HAP1 p.Arg116Trp (c.346C>T) is rare (popmax 0.556%, nfe) (gnomAD).

What do computational predictors say about HAP1 p.Arg116Trp (c.346C>T)?

AlphaMissense predicts likely benign (score 0.2065) — an in-silico prediction, not a clinical call.

HAP1 p.Arg116Trp

c.346C>T · rs189020240 · VCV3038751

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2065 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.556%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HAP1-related disorder

Computational evidence

Protein change
AlphaMissense	0.2065	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -7.52	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 0.48	GERP -1
Regional constraint	o/e 1.05	unconstrained · MANE · 9,930 bp · p 0.16 · regional, not allelic
Overall
CADD	22.5	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 0.556% European (non-Finnish) · 6,552/1,177,726 alleles

Filtering AF 0.545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.54%

Overall 0.449% 7,221/1,608,852 alleles · rare exomes 6,781/1,456,498 · genomes 440/152,354 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.556%	180
Amishnot grpmax-eligible	0.548%	182
Remaining individualsnot grpmax-eligible	0.457%	219
Admixed American	0.437%	229
Middle Eastern	0.413%	242
African / African-American	0.076%	1,316
South Asian	0.0276%	3,624
Finnishnot grpmax-eligible	0.0192%	5,206

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.Arg116Trp
Coding: c.346C>T
MANE Select: NM_177977
dbSNP: rs189020240
Type: single nucleotide variant
Location: chr17:41734289 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.28
Residue 116: the hap1 n-terminal domain

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

Disease context

HAP1-related disorder

Similar variants

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HAP1 p.Ala21= Likely benign same condition
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HAP1 p.Asp339Asn Likely benign same condition
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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-arg116trp (accessed [today's date]).

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