Is CSPG5 p.Ala125Pro (c.373G>C) pathogenic?

CSPG5 p.Ala125Pro (c.373G>C) is classified Uncertain significance in CSPG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely benign (0.1154); Very rare (popmax 0.00017%, nfe).

How common is CSPG5 p.Ala125Pro (c.373G>C) in the general population?

CSPG5 p.Ala125Pro (c.373G>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about CSPG5 p.Ala125Pro (c.373G>C)?

AlphaMissense predicts likely benign (score 0.1154) — an in-silico prediction, not a clinical call.

CSPG5 p.Ala125Pro

c.373G>C · VCV4657286

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1154 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1154	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -6.42	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 2.1	GERP 1.2, phastCons 0.97
Regional constraint	o/e 0.89	unconstrained · MANE · 16 kb · p 0.0046 · regional, not allelic
Overall
CADD	22.0	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 0.00017% European (non-Finnish) · 2/1,177,546 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000138% 2/1,454,106 alleles · very rare

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: CSPG5
Protein: p.Ala125Pro
Coding: c.373G>C
MANE Select: NM_006574
Type: single nucleotide variant
Location: chr3:47577653 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.52

Full CSPG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSPG5 p.Thr126= Benign ★★ same type
CSPG5 c.1458+20C>A Uncertain significance ★ ⚠ same type
CSPG5 c.1458+26G>T Uncertain significance ★ ⚠ same type
CSPG5 c.1458+38C>T Uncertain significance ★ ⚠ same type
CSPG5 c.1458+40C>T Uncertain significance ★ ⚠ same type
CSPG5 c.1458+46C>T Uncertain significance ★ ⚠ same type
CSPG5 c.1458+62A>C Uncertain significance ★ ⚠ same type
CSPG5 c.1458+62A>G 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/cspg5-p-ala125pro (accessed [today's date]).

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