Is PSPC1 p.Pro488His (c.1463C>A) pathogenic?

PSPC1 p.Pro488His (c.1463C>A) is classified Uncertain significance in PSPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). AlphaMissense: likely benign (0.2277); Ultra-rare (popmax 0.0307%, sas).

How common is PSPC1 p.Pro488His (c.1463C>A) in the general population?

PSPC1 p.Pro488His (c.1463C>A) is ultra-rare (popmax 0.0307%, sas) (gnomAD).

What do computational predictors say about PSPC1 p.Pro488His (c.1463C>A)?

AlphaMissense predicts likely benign (score 0.2277) — an in-silico prediction, not a clinical call.

PSPC1 p.Pro488His

c.1463C>A · VCV3784503

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2277 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2277	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -9.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 2,648 bp · p 4.4e-23 · regional, not allelic
Overall
CADD	24.0	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 0.0307% South Asian · 28/91,084 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.00173% 28/1,613,954 alleles · ultra-rare exomes 24/1,461,724 · genomes 4/152,230 · 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: PSPC1
Protein: p.Pro488His
Coding: c.1463C>A
MANE Select: NM_001354909
Type: single nucleotide variant
Location: chr13:19703284 (GRCh38)
Gene constraint: LOEUF 0.477 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 74.41 · 3 PDB
Residue 488: the 'disordered' region

Full PSPC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PSPC1 p.Ala156Thr Uncertain significance ★ ⚠ same type
PSPC1 p.Ala281Gly Uncertain significance ★ ⚠ same type
PSPC1 p.Ala300Val Uncertain significance ★ ⚠ same type
PSPC1 p.Ala407Gly Uncertain significance ★ ⚠ same type
PSPC1 p.Ala411Ser Uncertain significance ★ ⚠ same type
PSPC1 p.Ala42Asp Uncertain significance ★ ⚠ same type
PSPC1 p.Arg20Leu Uncertain significance ★ ⚠ same type
PSPC1 p.Arg228His 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/pspc1-p-pro488his (accessed [today's date]).

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