Is HPD p.Thr294Ala (c.880A>G) pathogenic?

HPD p.Thr294Ala (c.880A>G) is classified Uncertain significance in HPD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-12). AlphaMissense: likely benign (0.0682); Ultra-rare (popmax 0.02%, amr).

How common is HPD p.Thr294Ala (c.880A>G) in the general population?

HPD p.Thr294Ala (c.880A>G) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about HPD p.Thr294Ala (c.880A>G)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

HPD p.Thr294Ala

c.880A>G · rs777465411 · VCV1312275

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -9.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -0.47, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 19 kb · p 0.004 · regional, not allelic
Overall
CADD	14.35	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 0.02% Admixed American · 12/59,982 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.000805% 13/1,613,974 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	4,999
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: HPD
Protein: p.Thr294Ala
Coding: c.880A>G
MANE Select: NM_002150
dbSNP: rs777465411
Type: single nucleotide variant
Location: chr12:121843784 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB
Residue 294: a UniProt-annotated variant site (in tyrsn3; likely pathogenic); the voc 2 domain; an α-helix

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

Similar variants

HPD p.Thr294Met Uncertain significance ★ ⚠ same residue
HPD p.Thr294= Likely benign ★ same residue
HPD p.Arg225Ter Pathogenic/Likely pathogenic ★★ same type
HPD p.Gln205Ter Pathogenic/Likely pathogenic ★★ same type
HPD p.Tyr160Cys Likely pathogenic ★★ ⚠ same type
HPD c.198+3G>A Uncertain significance ★★ same type
HPD p.Ala230Thr Uncertain significance ★★ ⚠ same type
HPD p.Arg111Trp Uncertain significance ★★ ⚠ 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/hpd-p-thr294ala (accessed [today's date]).

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