Is PSMD4 p.Pro175Ser (c.523C>T) pathogenic?

PSMD4 p.Pro175Ser (c.523C>T) is classified Uncertain significance in PSMD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). AlphaMissense: ambiguous (0.3549); Absent from gnomAD v4.1.

How common is PSMD4 p.Pro175Ser (c.523C>T) in the general population?

PSMD4 p.Pro175Ser (c.523C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PSMD4 p.Pro175Ser (c.523C>T)?

AlphaMissense predicts ambiguous (score 0.3549) — an in-silico prediction, not a clinical call.

PSMD4 p.Pro175Ser

c.523C>T · rs2528415758 · VCV3220450

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3549 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3549	ambiguous
REVEL	0.199	benign-leaning
SaProt	LLR -12.74	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 11 kb · p 7.2e-11 · regional, not allelic
Overall
CADD	24.8	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

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: PSMD4
Protein: p.Pro175Ser
Coding: c.523C>T
MANE Select: NM_002810
dbSNP: rs2528415758
Type: single nucleotide variant
Location: chr1:151265478 (GRCh38)
Gene constraint: LOEUF 0.295 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.72 · 133 PDB
Residue 175: the vwfa domain; a β-strand

Full PSMD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PSMD4 p.Thr250= Benign ★★ same type
PSMD4 p.Val92= Benign/Likely benign ★★ same type
PSMD4 p.Ala259Asp Uncertain significance ★ ⚠ same type
PSMD4 p.Ala259Thr Uncertain significance ★ ⚠ same type
PSMD4 p.Ala303Val Uncertain significance ★ ⚠ same type
PSMD4 p.Ala55Ser Uncertain significance ★ ⚠ same type
PSMD4 p.Arg108His Uncertain significance ★ ⚠ same type
PSMD4 p.Arg230Trp Uncertain significance ★ ⚠ same type

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/psmd4-p-pro175ser (accessed [today's date]).

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