Is HPSE2 p.Arg341Trp (c.1021C>T) pathogenic?

HPSE2 p.Arg341Trp (c.1021C>T) is classified Uncertain significance in HPSE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-14). AlphaMissense: ambiguous (0.3729); Very rare (popmax 0.00988%, sas); Associated with Inborn genetic diseases.

What condition is associated with HPSE2 p.Arg341Trp (c.1021C>T)?

HPSE2 p.Arg341Trp (c.1021C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HPSE2 p.Arg341Trp (c.1021C>T) in the general population?

HPSE2 p.Arg341Trp (c.1021C>T) is very rare (popmax 0.00988%, sas) (gnomAD).

What do computational predictors say about HPSE2 p.Arg341Trp (c.1021C>T)?

AlphaMissense predicts ambiguous (score 0.3729) — an in-silico prediction, not a clinical call.

HPSE2 p.Arg341Trp

c.1021C>T · VCV3526534

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3729 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3729	ambiguous
REVEL	0.238	benign-leaning
SaProt	LLR -10.13	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 776 kb · p 0.31 · regional, not allelic
Overall
CADD	33.0	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 0.00988% South Asian · 9/91,052 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00376%

Overall 0.00211% 34/1,613,034 alleles · very rare exomes 32/1,461,086 · genomes 2/151,948 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,117
African / African-American	0.00267%	37,411
European (non-Finnish)	0.00178%	56,162
Admixed American	0.00167%	59,958
Remaining individualsnot grpmax-eligible	0.0016%	62,462

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.Arg341Trp
Coding: c.1021C>T
MANE Select: NM_021828
Type: single nucleotide variant
Location: chr10:98641924 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HPSE2 p.Arg341Gln Uncertain significance ★ ⚠ same residue
HPSE2 p.Arg267Trp Uncertain significance ★★ same condition
HPSE2 p.Arg494His Uncertain significance ★★ ⚠ same condition
HPSE2 p.Arg494Leu Uncertain significance ★★ same condition
HPSE2 p.Arg590His Uncertain significance ★★ ⚠ same condition
HPSE2 p.Arg590Ser Uncertain significance ★★ ⚠ same condition
HPSE2 p.Asn237Ser Uncertain significance ★★ ⚠ same condition
HPSE2 p.Asp171Gly Uncertain significance ★★ ⚠ same condition

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-arg341trp (accessed [today's date]).

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