Is PSPC1 p.Pro381Ala (c.1141C>G) pathogenic?

PSPC1 p.Pro381Ala (c.1141C>G) is classified Uncertain significance in PSPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.098); Very rare (popmax 0.00769%, sas).

How common is PSPC1 p.Pro381Ala (c.1141C>G) in the general population?

PSPC1 p.Pro381Ala (c.1141C>G) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about PSPC1 p.Pro381Ala (c.1141C>G)?

AlphaMissense predicts likely benign (score 0.098) — an in-silico prediction, not a clinical call.

PSPC1 p.Pro381Ala

c.1141C>G · VCV4573428

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.098 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.098	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -7.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 25 kb · p 0.049 · regional, not allelic
Overall
CADD	22.5	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 0.00769% South Asian · 7/90,970 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00093% 15/1,613,266 alleles · very rare exomes 14/1,461,464 · genomes 1/151,802 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	12,996
European (non-Finnish)	0.000678%	147,463

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.Pro381Ala
Coding: c.1141C>G
MANE Select: NM_001354909
Type: single nucleotide variant
Location: chr13:19730256 (GRCh38)
Gene constraint: LOEUF 0.477 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 74.41 · 3 PDB

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-pro381ala (accessed [today's date]).

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