Is PDSS2 p.His321Pro (c.962A>C) pathogenic?

PDSS2 p.His321Pro (c.962A>C) is classified Uncertain significance in PDSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-24). AlphaMissense: likely pathogenic (0.9094); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PDSS2 p.His321Pro (c.962A>C)?

PDSS2 p.His321Pro (c.962A>C) is associated with Inborn genetic diseases (ClinVar).

How common is PDSS2 p.His321Pro (c.962A>C) in the general population?

PDSS2 p.His321Pro (c.962A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PDSS2 p.His321Pro (c.962A>C)?

AlphaMissense predicts likely pathogenic (score 0.9094) — an in-silico prediction, not a clinical call.

PDSS2 p.His321Pro

c.962A>C · VCV3887567

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9094 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9094	likely pathogenic · top 7% in PDSS2
REVEL	0.591	indeterminate
SaProt	LLR -14.03	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 305 kb · p 0.17 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PDSS2
Protein: p.His321Pro
Coding: c.962A>C
MANE Select: NM_020381
Type: single nucleotide variant
Location: chr6:107210485 (GRCh38)
Gene constraint: LOEUF 0.818 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.28

Full PDSS2 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

PDSS2 p.Arg366Cys Uncertain significance ★★ ⚠ same condition
PDSS2 p.Arg366His Uncertain significance ★★ ⚠ same condition
PDSS2 p.Asn201Ser Uncertain significance ★★ ⚠ same condition
PDSS2 p.Asn314Thr Uncertain significance ★★ ⚠ same condition
PDSS2 p.Asp175His Uncertain significance ★★ ⚠ same condition
PDSS2 p.Asp307Asn Uncertain significance ★★ ⚠ same condition
PDSS2 p.Leu111Ser Uncertain significance ★★ same condition
PDSS2 p.Met137Thr 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/pdss2-p-his321pro (accessed [today's date]).

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