Is PDSS1 p.Trp14Cys (c.42G>C) pathogenic?

PDSS1 p.Trp14Cys (c.42G>C) is classified Uncertain significance in PDSS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-07). AlphaMissense: likely benign (0.2806); Very rare (popmax 0.00039%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PDSS1 p.Trp14Cys (c.42G>C)?

PDSS1 p.Trp14Cys (c.42G>C) is associated with Inborn genetic diseases (ClinVar).

How common is PDSS1 p.Trp14Cys (c.42G>C) in the general population?

PDSS1 p.Trp14Cys (c.42G>C) is very rare (popmax 0.00039%, nfe) (gnomAD).

What do computational predictors say about PDSS1 p.Trp14Cys (c.42G>C)?

AlphaMissense predicts likely benign (score 0.2806) — an in-silico prediction, not a clinical call.

PDSS1 p.Trp14Cys

c.42G>C · rs1834909905 · VCV1206944

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2806 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00039%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2806	likely benign
REVEL	0.478	indeterminate
SaProt	LLR -7.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 7,645 bp · p 0.15 · regional, not allelic
Overall
CADD	26.6	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 0.00039% European (non-Finnish) · 4/1,026,016 alleles

Filtering AF 9.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.2e-05%

Overall 0.000309% 4/1,293,384 alleles · very rare exomes 3/1,141,396 · genomes 1/151,988 · 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: PDSS1
Protein: p.Trp14Cys
Coding: c.42G>C
MANE Select: NM_014317
dbSNP: rs1834909905
Type: single nucleotide variant
Location: chr10:26697753 (GRCh38)
Gene constraint: LOEUF 1.163 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.45

Full PDSS1 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

PDSS1 p.Trp14Ser Uncertain significance ★ ⚠ same residue
PDSS1 c.721+4C>T Uncertain significance ★★ same condition
PDSS1 p.Arg163Cys Uncertain significance ★★ ⚠ same condition
PDSS1 p.Arg221Gln Uncertain significance ★★ ⚠ same condition
PDSS1 p.Arg240His Uncertain significance ★★ ⚠ same condition
PDSS1 p.Arg353Trp Uncertain significance ★★ ⚠ same condition
PDSS1 p.Arg76Trp Uncertain significance ★★ ⚠ same condition
PDSS1 p.Gln365His 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/pdss1-p-trp14cys (accessed [today's date]).

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