Is HAP1 p.Arg399Trp (c.1195C>T) pathogenic?

HAP1 p.Arg399Trp (c.1195C>T) is classified Uncertain significance in HAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-23). AlphaMissense: likely benign (0.1186); Ultra-rare (popmax 0.0165%, mid).

How common is HAP1 p.Arg399Trp (c.1195C>T) in the general population?

HAP1 p.Arg399Trp (c.1195C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about HAP1 p.Arg399Trp (c.1195C>T)?

AlphaMissense predicts likely benign (score 0.1186) — an in-silico prediction, not a clinical call.

HAP1 p.Arg399Trp

c.1195C>T · rs573288812 · VCV2510741

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1186 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1186	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -8.71	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 1.2	GERP -1, phastCons 0.62
Regional constraint	o/e 1.05	unconstrained · MANE · 9,930 bp · p 0.16 · regional, not allelic
Overall
CADD	18.66	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0066%

Overall 0.00776% 125/1,611,258 alleles · ultra-rare exomes 116/1,458,976 · genomes 9/152,282 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
Admixed American	0.0117%	8,573
South Asian	0.00988%	10,119
European (non-Finnish)	0.00847%	11,800
East Asian	0.00669%	14,959
Remaining individualsnot grpmax-eligible	0.0064%	15,624
African / African-American	0.00133%	75,034

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.Arg399Trp
Coding: c.1195C>T
MANE Select: NM_177977
dbSNP: rs573288812
Type: single nucleotide variant
Location: chr17:41728206 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.28
Residue 399: the hap1 n-terminal domain

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

Similar variants

HAP1 p.Arg399Gln Likely benign ★ 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-arg399trp (accessed [today's date]).

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