Is CSPG4 p.Phe1749Ser (c.5246T>C) pathogenic?

CSPG4 p.Phe1749Ser (c.5246T>C) is classified Uncertain significance in CSPG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: likely pathogenic (0.9869); Very rare (popmax 0.0022%, amr).

How common is CSPG4 p.Phe1749Ser (c.5246T>C) in the general population?

CSPG4 p.Phe1749Ser (c.5246T>C) is very rare (popmax 0.0022%, amr) (gnomAD).

What do computational predictors say about CSPG4 p.Phe1749Ser (c.5246T>C)?

AlphaMissense predicts likely pathogenic (score 0.9869) — an in-silico prediction, not a clinical call.

CSPG4 p.Phe1749Ser

c.5246T>C · VCV3497883

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9869 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9869	likely pathogenic · top 1% in CSPG4
REVEL	0.479	indeterminate
SaProt	LLR -14.26	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.31	acceptor loss, 5 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 11	GERP 0.34, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 15 kb · p 3.1e-21 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0022% Admixed American · 1/45,366 alleles

Overall 7.44e-05% 1/1,344,558 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: CSPG4
Protein: p.Phe1749Ser
Coding: c.5246T>C
MANE Select: NM_001897
Type: single nucleotide variant
Location: chr15:75677273 (GRCh38)
Gene constraint: LOEUF 0.693 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.35 · 3 PDB
Residue 1749: the 'neurite growth inhibition' region; the 'cysteine-containing' region

Full CSPG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSPG4 p.Arg2169Trp Uncertain significance ★★ ⚠ same type
CSPG4 p.Arg1557His Likely benign ★★ same type
CSPG4 p.Ser1882= Likely benign ★★ same type
CSPG4 p.Thr305Met Benign ★★ ⚠ same type
CSPG4 p.Ala1116Val Uncertain significance ★ ⚠ same type
CSPG4 p.Ala1186Val Uncertain significance ★ ⚠ same type
CSPG4 p.Ala1212Val Uncertain significance ★ ⚠ same type
CSPG4 p.Ala121Thr 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/cspg4-p-phe1749ser (accessed [today's date]).

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