Is HAP1 p.Gln380Arg (c.1139A>G) pathogenic?

HAP1 p.Gln380Arg (c.1139A>G) is classified Uncertain significance in HAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-14). AlphaMissense: likely benign (0.2555); Ultra-rare (popmax 0.0263%, sas).

How common is HAP1 p.Gln380Arg (c.1139A>G) in the general population?

HAP1 p.Gln380Arg (c.1139A>G) is ultra-rare (popmax 0.0263%, sas) (gnomAD).

What do computational predictors say about HAP1 p.Gln380Arg (c.1139A>G)?

AlphaMissense predicts likely benign (score 0.2555) — an in-silico prediction, not a clinical call.

HAP1 p.Gln380Arg

c.1139A>G · VCV3523901

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2555 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0263%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2555	likely benign
REVEL	0.266	benign-leaning
SaProt	LLR -7.76	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 1.4	GERP 1.3, phastCons 0.98
Regional constraint	o/e 1.05	unconstrained · MANE · 9,930 bp · p 0.16 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0263% South Asian · 24/91,088 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00149% 24/1,613,680 alleles · ultra-rare exomes 22/1,461,330 · genomes 2/152,350 · joint denominator

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.Gln380Arg
Coding: c.1139A>G
MANE Select: NM_177977
Type: single nucleotide variant
Location: chr17:41728262 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.28
Residue 380: 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-gln380arg (accessed [today's date]).

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