Is HHAT p.Arg250Pro (c.749G>C) pathogenic?

HHAT p.Arg250Pro (c.749G>C) is classified Uncertain significance in HHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: likely pathogenic (0.6702); Very rare (popmax 0.0072%, nfe).

How common is HHAT p.Arg250Pro (c.749G>C) in the general population?

HHAT p.Arg250Pro (c.749G>C) is very rare (popmax 0.0072%, nfe) (gnomAD).

What do computational predictors say about HHAT p.Arg250Pro (c.749G>C)?

AlphaMissense predicts likely pathogenic (score 0.6702) — an in-silico prediction, not a clinical call.

HHAT p.Arg250Pro

c.749G>C · VCV4035020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6702 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0072%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6702	likely pathogenic
REVEL	0.845	moderately pathogenic-leaning
SaProt	LLR -13.07	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.4	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 325 kb · p 0.86 · regional, not allelic
Overall
CADD	27.4	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 0.0072% European (non-Finnish) · 85/1,179,940 alleles

Filtering AF 0.00596% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.00539% 87/1,613,888 alleles · very rare exomes 82/1,461,744 · genomes 5/152,144 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0072%	13,882
Admixed American	0.00167%	59,990
African / African-American	0.00133%	74,922

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.Arg250Pro
Coding: c.749G>C
MANE Select: NM_018194
Type: single nucleotide variant
Location: chr1:210418218 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.07 · 10 PDB
Residue 250: 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

Similar variants

HHAT p.Arg250His Uncertain significance ★ ⚠ same residue
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

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-arg250pro (accessed [today's date]).

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