Is HHAT p.Pro421Arg (c.1262C>G) pathogenic?

HHAT p.Pro421Arg (c.1262C>G) is classified Uncertain significance in HHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely benign (0.088); Absent from gnomAD v4.1.

How common is HHAT p.Pro421Arg (c.1262C>G) in the general population?

HHAT p.Pro421Arg (c.1262C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HHAT p.Pro421Arg (c.1262C>G)?

AlphaMissense predicts likely benign (score 0.088) — an in-silico prediction, not a clinical call.

HHAT p.Pro421Arg

c.1262C>G · VCV3857731

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.088 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.088	likely benign
REVEL	0.402	indeterminate
SaProt	LLR -8.81	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 2.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 325 kb · p 0.86 · regional, not allelic
Overall
CADD	23.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HHAT
Protein: p.Pro421Arg
Coding: c.1262C>G
MANE Select: NM_018194
Type: single nucleotide variant
Location: chr1:210623542 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.07 · 10 PDB
Residue 421: 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-pro421arg (accessed [today's date]).

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