Is HAP1 p.Trp104Ter (c.311G>A) pathogenic?

HAP1 p.Trp104Ter (c.311G>A) is classified Benign in HAP1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-29). Low-frequency (popmax 1.05%, eas); Associated with HAP1-related disorder.

What condition is associated with HAP1 p.Trp104Ter (c.311G>A)?

HAP1 p.Trp104Ter (c.311G>A) is associated with HAP1-related disorder (ClinVar).

How common is HAP1 p.Trp104Ter (c.311G>A) in the general population?

HAP1 p.Trp104Ter (c.311G>A) is low-frequency (popmax 1.05%, eas) (gnomAD).

HAP1 p.Trp104Ter

c.311G>A · rs181373328 · VCV3049924

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

low-frequency (popmax 1.05%, eas)

Conditions

HAP1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 11
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.58	GERP -0.86, phastCons 0.21
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.05% East Asian · 468/44,750 alleles

Filtering AF 0.968% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.937%

Overall 0.0306% 493/1,609,056 alleles · low-frequency exomes 436/1,456,696 · genomes 57/152,360 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.05%	96
South Asian	0.0198%	5,045
Remaining individualsnot grpmax-eligible	0.0113%	8,885

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.Trp104Ter
Coding: c.311G>A
MANE Select: NM_177977
dbSNP: rs181373328
Type: single nucleotide variant
Location: chr17:41734324 (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

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.Ala505Val Benign same condition
HAP1 p.Arg116Trp Likely benign same condition
HAP1 p.Asp339Asn Likely benign same condition
HAP1 p.Leu408Phe 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-trp104ter (accessed [today's date]).

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