Is HPSE2 p.Arg466Trp (c.1396C>T) pathogenic?

HPSE2 p.Arg466Trp (c.1396C>T) is classified Uncertain significance in HPSE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-12). AlphaMissense: likely pathogenic (0.8306); Very rare (popmax 0.00659%, sas); Associated with Inborn genetic diseases.

What condition is associated with HPSE2 p.Arg466Trp (c.1396C>T)?

HPSE2 p.Arg466Trp (c.1396C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HPSE2 p.Arg466Trp (c.1396C>T) in the general population?

HPSE2 p.Arg466Trp (c.1396C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about HPSE2 p.Arg466Trp (c.1396C>T)?

AlphaMissense predicts likely pathogenic (score 0.8306) — an in-silico prediction, not a clinical call.

HPSE2 p.Arg466Trp

c.1396C>T · VCV3526544

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8306 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8306	likely pathogenic
REVEL	0.29	benign-leaning
SaProt	LLR -9.15	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP -3.3, phastCons 0.79
Regional constraint	o/e 0.96	unconstrained · MANE · 776 kb · p 0.31 · regional, not allelic
Overall
CADD	24.3	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 0.00659% South Asian · 6/91,084 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00062% 10/1,614,188 alleles · very rare exomes 10/1,461,870 · genomes 0/152,318 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,181
European (non-Finnish)	0.000339%	295,009

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.Arg466Trp
Coding: c.1396C>T
MANE Select: NM_021828
Type: single nucleotide variant
Location: chr10:98490121 (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.Arg466Gln 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-arg466trp (accessed [today's date]).

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