Is HAP1 p.Gly604Arg (c.1810G>A) pathogenic?

HAP1 p.Gly604Arg (c.1810G>A) is classified Benign in HAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-04-30). AlphaMissense: likely benign (0.1396); Low-frequency (popmax 4.63%, afr).

How common is HAP1 p.Gly604Arg (c.1810G>A) in the general population?

HAP1 p.Gly604Arg (c.1810G>A) is low-frequency (popmax 4.63%, afr) (gnomAD).

What do computational predictors say about HAP1 p.Gly604Arg (c.1810G>A)?

AlphaMissense predicts likely benign (score 0.1396) — an in-silico prediction, not a clinical call.

HAP1 p.Gly604Arg

c.1810G>A · rs34044330 · VCV781300

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1396 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.63%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1396	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -5.70	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 -0.098	GERP 0.1
Regional constraint	o/e 1.05	unconstrained · MANE · 9,930 bp · p 0.16 · regional, not allelic
Overall
CADD	4.371	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM G656R vs ClinVar G604R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.63% African / African-American · 3,462/74,812 alleles

Filtering AF 4.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.45%

Overall 0.264% 4,234/1,600,942 alleles · low-frequency exomes 2,173/1,448,748 · genomes 2,061/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.63%	22
Middle Eastern	0.819%	122
Remaining individualsnot grpmax-eligible	0.382%	262
Admixed American	0.366%	273
East Asian	0.0382%	2,618
South Asian	0.033%	3,029
European (non-Finnish)	0.0188%	5,318
Ashkenazi Jewishnot grpmax-eligible	0.00678%	14,746
Finnishnot grpmax-eligible	0.00159%	63,008

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.Gly604Arg
Coding: c.1810G>A
MANE Select: NM_177977
dbSNP: rs34044330
Type: single nucleotide variant
Location: chr17:41724751 (GRCh38)
Gene constraint: LOEUF 1.31 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.28
Residue 656 UniProt numbering: a UniProt-annotated variant site (in)

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.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
HAP1 p.Val369Ala 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-gly604arg (accessed [today's date]).

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