Is HHAT p.His428= (c.1284C>T) pathogenic?

HHAT p.His428= (c.1284C>T) is classified Likely benign in HHAT (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-05). Ultra-rare (popmax 0.0669%, eas); Associated with HHAT-related disorder.

What condition is associated with HHAT p.His428= (c.1284C>T)?

HHAT p.His428= (c.1284C>T) is associated with HHAT-related disorder (ClinVar).

How common is HHAT p.His428= (c.1284C>T) in the general population?

HHAT p.His428= (c.1284C>T) is ultra-rare (popmax 0.0669%, eas) (gnomAD).

HHAT p.His428=

c.1284C>T · rs117382486 · VCV3041338

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0669%, eas)

Conditions

HHAT-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -16	GERP -4.8
Overall
CADD	0.271	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0669% East Asian · 30/44,870 alleles

Filtering AF 0.0481% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0417%

Overall 0.00551% 89/1,614,070 alleles · ultra-rare exomes 79/1,461,818 · genomes 10/152,252 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0669%	1,496
African / African-American	0.00933%	10,719
European (non-Finnish)	0.00407%	24,583
Remaining individualsnot grpmax-eligible	0.0032%	31,252
Admixed American	0.00167%	60,004
South Asian	0.0011%	91,060

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: HHAT
Protein: p.His428=
Coding: c.1284C>T
MANE Select: NM_018194
dbSNP: rs117382486
Type: single nucleotide variant
Location: chr1:210623564 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.07 · 10 PDB
Residue 428: an α-helix; a binding site; a UniProt-annotated variant site (in nnms; uncertain significance)

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

Disease context

HHAT-related disorder

Similar variants

HHAT p.His428Tyr Uncertain significance ★ ⚠ same residue
HHAT c.-57G>C Likely benign same condition
HHAT c.-87C>T Likely benign same condition
HHAT p.Ala308Thr Uncertain significance ★★ ⚠ same type
HHAT p.Arg176His Uncertain significance ★★ ⚠ same type
HHAT p.Arg403Trp Uncertain significance ★★ ⚠ same type
HHAT p.His379Tyr Uncertain significance ★★ ⚠ same type
HHAT c.1245+19G>C 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/hhat-p-his428 (accessed [today's date]).

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