Is HPSE2 p.Arg308Gln (c.923G>A) pathogenic?

HPSE2 p.Arg308Gln (c.923G>A) is classified Uncertain significance in HPSE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-05). AlphaMissense: likely benign (0.2313); Very rare (popmax 0.00669%, eas); Associated with Inborn genetic diseases.

What condition is associated with HPSE2 p.Arg308Gln (c.923G>A)?

HPSE2 p.Arg308Gln (c.923G>A) is associated with Inborn genetic diseases (ClinVar).

How common is HPSE2 p.Arg308Gln (c.923G>A) in the general population?

HPSE2 p.Arg308Gln (c.923G>A) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about HPSE2 p.Arg308Gln (c.923G>A)?

AlphaMissense predicts likely benign (score 0.2313) — an in-silico prediction, not a clinical call.

HPSE2 p.Arg308Gln

c.923G>A · rs761701445 · VCV2393575

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2313 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2313	likely benign
REVEL	0.327	indeterminate
SaProt	LLR -4.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 776 kb · p 0.31 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00669% East Asian · 3/44,850 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00403% 65/1,613,486 alleles · very rare exomes 60/1,461,522 · genomes 5/151,964 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,950
South Asian	0.00659%	15,178
Remaining individualsnot grpmax-eligible	0.0064%	15,616
European (non-Finnish)	0.00407%	24,581
Admixed American	0.00334%	29,944
Finnishnot grpmax-eligible	0.00156%	63,964
African / African-American	0.00134%	74,852

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.Arg308Gln
Coding: c.923G>A
MANE Select: NM_021828
dbSNP: rs761701445
Type: single nucleotide variant
Location: chr10:98721690 (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.Arg308Trp 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-arg308gln (accessed [today's date]).

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