Is HAT1 p.Arg330Ser (c.990G>C) pathogenic?

HAT1 p.Arg330Ser (c.990G>C) is classified Uncertain significance in HAT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely pathogenic (0.9621); Ultra-rare (popmax 0.0137%, afr).

How common is HAT1 p.Arg330Ser (c.990G>C) in the general population?

HAT1 p.Arg330Ser (c.990G>C) is ultra-rare (popmax 0.0137%, afr) (gnomAD).

What do computational predictors say about HAT1 p.Arg330Ser (c.990G>C)?

AlphaMissense predicts likely pathogenic (score 0.9621) — an in-silico prediction, not a clinical call.

HAT1 p.Arg330Ser

c.990G>C · VCV4033718

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9621 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9621	likely pathogenic · top 7% in HAT1
REVEL	0.485	indeterminate
SaProt	LLR -12.36	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.17	GERP -2.8, phastCons 0.81
Regional constraint	o/e 0.81	unconstrained · MANE · 61 kb · p 1.8e-05 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0137% African / African-American · 10/72,736 alleles

Filtering AF 0.00743% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00565%

Overall 0.000966% 15/1,552,338 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0137%	7,274
South Asian	0.00117%	85,746
European (non-Finnish)	0.000352%	284,140

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: HAT1
Protein: p.Arg330Ser
Coding: c.990G>C
MANE Select: NM_003642
Type: single nucleotide variant
Location: chr2:171979261 (GRCh38)
Gene constraint: LOEUF 1.439 · pLI 0.37 (gnomAD)
Structure: AlphaFold pLDDT 93.01 · 3 PDB
Residue 330: an α-helix

Full HAT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HAT1 p.Ala32Thr Uncertain significance ★ same type
HAT1 p.Arg349Gly Uncertain significance ★ ⚠ same type
HAT1 p.Arg349Lys Uncertain significance ★ ⚠ same type
HAT1 p.Arg410Trp Uncertain significance ★ ⚠ same type
HAT1 p.Arg411Cys Uncertain significance ★ ⚠ same type
HAT1 p.Asn122Lys Uncertain significance ★ ⚠ same type
HAT1 p.Asp47Gly Uncertain significance ★ ⚠ same type
HAT1 p.Cys120Ser Uncertain significance ★ ⚠ 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/hat1-p-arg330ser (accessed [today's date]).

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