Is PDSS2 p.Cys263Arg (c.787T>C) pathogenic?

PDSS2 p.Cys263Arg (c.787T>C) is classified Uncertain significance in PDSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). AlphaMissense: likely pathogenic (0.9925); Very rare (popmax 0.000509%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PDSS2 p.Cys263Arg (c.787T>C)?

PDSS2 p.Cys263Arg (c.787T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PDSS2 p.Cys263Arg (c.787T>C) in the general population?

PDSS2 p.Cys263Arg (c.787T>C) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about PDSS2 p.Cys263Arg (c.787T>C)?

AlphaMissense predicts likely pathogenic (score 0.9925) — an in-silico prediction, not a clinical call.

PDSS2 p.Cys263Arg

c.787T>C · VCV3930488

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9925	likely pathogenic · top 1% in PDSS2
REVEL	0.811	moderately pathogenic-leaning
SaProt	LLR -15.45	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 305 kb · p 0.17 · regional, not allelic
Overall
CADD	29.7	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

Grpmax group 0.000509% European (non-Finnish) · 6/1,179,872 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,994 alleles · very rare exomes 6/1,461,674 · genomes 0/152,320 · joint denominator

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: PDSS2
Protein: p.Cys263Arg
Coding: c.787T>C
MANE Select: NM_020381
Type: single nucleotide variant
Location: chr6:107212198 (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-cys263arg (accessed [today's date]).

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