Is HPD p.Gly154Ser (c.460G>A) pathogenic?

HPD p.Gly154Ser (c.460G>A) is classified Uncertain significance in HPD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-16). AlphaMissense: likely benign (0.32); Very rare (popmax 0.00223%, eas).

How common is HPD p.Gly154Ser (c.460G>A) in the general population?

HPD p.Gly154Ser (c.460G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about HPD p.Gly154Ser (c.460G>A)?

AlphaMissense predicts likely benign (score 0.32) — an in-silico prediction, not a clinical call.

HPD p.Gly154Ser

c.460G>A · rs1450141568 · VCV2682574

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.32 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.32	likely benign
REVEL	0.535	indeterminate
SaProt	LLR -9.26	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 19 kb · p 0.004 · regional, not allelic
Overall
CADD	26.0	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 0.00223% East Asian · 1/44,872 alleles

Overall 0.000137% 2/1,461,750 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,872
South Asian	0.0011%	91,068

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.Gly154Ser
Coding: c.460G>A
MANE Select: NM_002150
dbSNP: rs1450141568
Type: single nucleotide variant
Location: chr12:121849745 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB
Residue 154: a β-strand

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

Similar variants

HPD p.Gly154Arg Uncertain significance ★ ⚠ 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
HPD p.Arg119Gln 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-gly154ser (accessed [today's date]).

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