Is HPSE p.Pro226Ser (c.676C>T) pathogenic?

HPSE p.Pro226Ser (c.676C>T) is classified Uncertain significance in HPSE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: likely pathogenic (0.8971); Very rare (popmax 0.00553%, nfe).

How common is HPSE p.Pro226Ser (c.676C>T) in the general population?

HPSE p.Pro226Ser (c.676C>T) is very rare (popmax 0.00553%, nfe) (gnomAD).

What do computational predictors say about HPSE p.Pro226Ser (c.676C>T)?

AlphaMissense predicts likely pathogenic (score 0.8971) — an in-silico prediction, not a clinical call.

HPSE p.Pro226Ser

c.676C>T · VCV4036177

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8971 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00553%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8971	likely pathogenic
REVEL	0.66	pathogenic-leaning
SaProt	LLR -11.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 39 kb · p 0.8 · regional, not allelic
Overall
CADD	27.5	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 0.00553% European (non-Finnish) · 65/1,176,314 alleles

Filtering AF 0.00444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00405%

Overall 0.00411% 66/1,607,364 alleles · very rare exomes 63/1,455,200 · genomes 3/152,164 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00553%	18,097
Finnishnot grpmax-eligible	0.00156%	63,964

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: HPSE
Protein: p.Pro226Ser
Coding: c.676C>T
MANE Select: NM_001098540
Type: single nucleotide variant
Location: chr4:83310888 (GRCh38)
Gene constraint: LOEUF 1.066 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.02 · 58 PDB
Residue 226: an α-helix

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

Similar variants

HPSE c.673+8C>A Benign ★★ same type
HPSE p.Gly370Asp Likely benign ★★ same type
HPSE p.Ala177Gly Uncertain significance ★ ⚠ same type
HPSE p.Ala204Thr Uncertain significance ★ ⚠ same type
HPSE p.Ala285Thr Uncertain significance ★ ⚠ same type
HPSE p.Ala305Thr Uncertain significance ★ ⚠ same type
HPSE p.Ala84Thr Uncertain significance ★ ⚠ same type
HPSE p.Arg303Trp 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/hpse-p-pro226ser (accessed [today's date]).

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