Is HAT1 p.Ser128Phe (c.383C>T) pathogenic?

HAT1 p.Ser128Phe (c.383C>T) is classified Uncertain significance in HAT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-09). AlphaMissense: likely benign (0.1742); Very rare (popmax 0.00017%, nfe).

How common is HAT1 p.Ser128Phe (c.383C>T) in the general population?

HAT1 p.Ser128Phe (c.383C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about HAT1 p.Ser128Phe (c.383C>T)?

AlphaMissense predicts likely benign (score 0.1742) — an in-silico prediction, not a clinical call.

HAT1 p.Ser128Phe

c.383C>T · rs1305322223 · VCV2227991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1742	likely benign
REVEL	0.449	indeterminate
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 61 kb · p 1.8e-05 · regional, not allelic
Overall
CADD	26.9	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 0.00017% European (non-Finnish) · 2/1,176,940 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,610,326 alleles · very rare

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.Ser128Phe
Coding: c.383C>T
MANE Select: NM_003642
dbSNP: rs1305322223
Type: single nucleotide variant
Location: chr2:171965411 (GRCh38)
Gene constraint: LOEUF 1.439 · pLI 0.37 (gnomAD)
Structure: AlphaFold pLDDT 93.01 · 3 PDB
Residue 128: 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.Arg330Ser 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

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-ser128phe (accessed [today's date]).

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