Is HPSE2 p.Ser243Cys (c.727A>T) pathogenic?

HPSE2 p.Ser243Cys (c.727A>T) is classified Likely benign in HPSE2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-01). AlphaMissense: ambiguous (0.408); Rare (popmax 0.374%, eas).

How common is HPSE2 p.Ser243Cys (c.727A>T) in the general population?

HPSE2 p.Ser243Cys (c.727A>T) is rare (popmax 0.374%, eas) (gnomAD).

What do computational predictors say about HPSE2 p.Ser243Cys (c.727A>T)?

AlphaMissense predicts ambiguous (score 0.408) — an in-silico prediction, not a clinical call.

HPSE2 p.Ser243Cys

c.727A>T · rs188784527 · VCV726975

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.408 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.374%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.408	ambiguous
REVEL	0.172	moderately benign-leaning
SaProt	LLR -10.87	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 776 kb · p 0.31 · regional, not allelic
Overall
CADD	28.0	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 0.374% East Asian · 168/44,870 alleles

Filtering AF 0.328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.31%

Overall 0.0128% 206/1,614,086 alleles · rare exomes 171/1,461,796 · genomes 35/152,290 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.374%	267
South Asian	0.0263%	3,795
Remaining individualsnot grpmax-eligible	0.0176%	5,682
Admixed American	0.00167%	60,022
European (non-Finnish)	0.000169%	589,977

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: HPSE2
Protein: p.Ser243Cys
Coding: c.727A>T
MANE Select: NM_021828
dbSNP: rs188784527
Type: single nucleotide variant
Location: chr10:98743940 (GRCh38)
Gene constraint: LOEUF 0.837 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.90

Full HPSE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HPSE2 c.1099-1G>A Pathogenic ★★ same type
HPSE2 c.291-1G>T Likely pathogenic ★★ same type
HPSE2 p.Arg153Ter Pathogenic/Likely pathogenic ★★ same type
HPSE2 p.Arg506Ter Pathogenic/Likely pathogenic ★★ same type
HPSE2 p.Arg267Trp Uncertain significance ★★ same type
HPSE2 p.Arg272Gln Uncertain significance ★★ ⚠ same type
HPSE2 p.Arg352His Uncertain significance ★★ ⚠ same type
HPSE2 p.Arg494His 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/hpse2-p-ser243cys (accessed [today's date]).

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