Is HPD p.Arg225Gln (c.674G>A) pathogenic?

HPD p.Arg225Gln (c.674G>A) is classified Uncertain significance in HPD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: ambiguous (0.3591); Very rare (popmax 0.00333%, amr).

How common is HPD p.Arg225Gln (c.674G>A) in the general population?

HPD p.Arg225Gln (c.674G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about HPD p.Arg225Gln (c.674G>A)?

AlphaMissense predicts ambiguous (score 0.3591) — an in-silico prediction, not a clinical call.

HPD p.Arg225Gln

c.674G>A · rs753428608 · VCV2643489

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3591 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3591	ambiguous
REVEL	0.715	pathogenic-leaning
SaProt	LLR -11.01	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 19 kb · p 0.004 · regional, not allelic
Overall
CADD	27.2	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 0.00333% Admixed American · 2/59,990 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000372% 6/1,614,024 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,995
European (non-Finnish)	0.000339%	295,008

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.Arg225Gln
Coding: c.674G>A
MANE Select: NM_002150
dbSNP: rs753428608
Type: single nucleotide variant
Location: chr12:121847137 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB
Residue 225: a UniProt-annotated variant site (in tyrsn3; likely pathogenic); the voc 2 domain; a β-strand

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

Similar variants

HPD p.Arg225Ter Pathogenic/Likely pathogenic ★★ same residue
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
HPD p.Arg119Gln Uncertain significance ★★ ⚠ same type
HPD p.Arg279Cys 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-arg225gln (accessed [today's date]).

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