Is HHAT p.Phe366Leu (c.1098T>G) pathogenic?

HHAT p.Phe366Leu (c.1098T>G) is classified Uncertain significance in HHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-06). AlphaMissense: likely benign (0.2609); Ultra-rare (popmax 0.0694%, afr).

How common is HHAT p.Phe366Leu (c.1098T>G) in the general population?

HHAT p.Phe366Leu (c.1098T>G) is ultra-rare (popmax 0.0694%, afr) (gnomAD).

What do computational predictors say about HHAT p.Phe366Leu (c.1098T>G)?

AlphaMissense predicts likely benign (score 0.2609) — an in-silico prediction, not a clinical call.

HHAT p.Phe366Leu

c.1098T>G · rs150462339 · VCV2591782

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2609 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0694%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2609	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -6.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.01	GERP -4.8, phastCons 0.95
Regional constraint	o/e 1.01	unconstrained · MANE · 325 kb · p 0.86 · regional, not allelic
Overall
CADD	8.143	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 0.0694% African / African-American · 52/74,922 alleles

Filtering AF 0.0543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.049%

Overall 0.00359% 58/1,614,048 alleles · ultra-rare exomes 28/1,461,854 · genomes 30/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0694%	1,441
Admixed American	0.00333%	30,006
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000254%	393,340

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.Phe366Leu
Coding: c.1098T>G
MANE Select: NM_018194
dbSNP: rs150462339
Type: single nucleotide variant
Location: chr1:210587952 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.07 · 10 PDB
Residue 366: an α-helix; a UniProt-annotated variant site (in nnms; uncertain significance)

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

Similar variants

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
HHAT c.159+15C>A Benign ★★ same type
HHAT p.Ala389= Benign ★★ same type
HHAT p.Arg176Cys 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-phe366leu (accessed [today's date]).

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