Is HHAT p.Arg131Pro (c.392G>C) pathogenic?

HHAT p.Arg131Pro (c.392G>C) is classified Likely benign in HHAT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-04). AlphaMissense: likely benign (0.3175); Rare (popmax 0.212%, eas).

How common is HHAT p.Arg131Pro (c.392G>C) in the general population?

HHAT p.Arg131Pro (c.392G>C) is rare (popmax 0.212%, eas) (gnomAD).

What do computational predictors say about HHAT p.Arg131Pro (c.392G>C)?

AlphaMissense predicts likely benign (score 0.3175) — an in-silico prediction, not a clinical call.

HHAT p.Arg131Pro

c.392G>C · VCV4802161

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3175 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.212%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3175	likely benign
REVEL	0.524	indeterminate
SaProt	LLR -14.31	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP -2.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 325 kb · p 0.86 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.212% East Asian · 95/44,872 alleles

Filtering AF 0.177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.164%

Overall 0.0158% 255/1,614,094 alleles · rare exomes 242/1,461,878 · genomes 13/152,216 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.212%	472
South Asian	0.0253%	3,960
Finnishnot grpmax-eligible	0.0109%	9,147
European (non-Finnish)	0.0105%	9,516
Remaining individualsnot grpmax-eligible	0.0096%	10,418

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.Arg131Pro
Coding: c.392G>C
MANE Select: NM_018194
Type: single nucleotide variant
Location: chr1:210400586 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.07 · 10 PDB
Residue 131: the 'essential for palmitoylation of shh' region; 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.Arg131Trp 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-arg131pro (accessed [today's date]).

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