Is HPSE2 p.Arg590Ser (c.1768C>A) pathogenic?

HPSE2 p.Arg590Ser (c.1768C>A) is classified Uncertain significance in HPSE2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-11). AlphaMissense: likely pathogenic (0.8119); Very rare (popmax 0.0061%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HPSE2 p.Arg590Ser (c.1768C>A)?

HPSE2 p.Arg590Ser (c.1768C>A) is associated with Inborn genetic diseases (ClinVar).

How common is HPSE2 p.Arg590Ser (c.1768C>A) in the general population?

HPSE2 p.Arg590Ser (c.1768C>A) is very rare (popmax 0.0061%, nfe) (gnomAD).

What do computational predictors say about HPSE2 p.Arg590Ser (c.1768C>A)?

AlphaMissense predicts likely pathogenic (score 0.8119) — an in-silico prediction, not a clinical call.

HPSE2 p.Arg590Ser

c.1768C>A · rs745695570 · VCV2172514

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8119 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0061%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8119	likely pathogenic
REVEL	0.267	benign-leaning
SaProt	LLR -2.21	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 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 776 kb · p 0.31 · regional, not allelic
Overall
CADD	27.7	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 0.0061% European (non-Finnish) · 72/1,180,008 alleles

Filtering AF 0.00495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00455%

Overall 0.00477% 77/1,613,982 alleles · very rare exomes 68/1,461,870 · genomes 9/152,112 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0061%	16,389
African / African-American	0.00401%	24,968
Remaining individualsnot grpmax-eligible	0.0016%	62,482
Finnishnot grpmax-eligible	0.00156%	64,036

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.Arg590Ser
Coding: c.1768C>A
MANE Select: NM_021828
dbSNP: rs745695570
Type: single nucleotide variant
Location: chr10:98459585 (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.Arg590His 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.Asn237Ser Uncertain significance ★★ ⚠ same condition
HPSE2 p.Asp171Gly Uncertain significance ★★ ⚠ same condition
HPSE2 p.Cys21Tyr Uncertain significance ★★ ⚠ same condition
HPSE2 p.Ile87Thr 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-arg590ser (accessed [today's date]).

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