Is HSPG2 p.Cys1237Phe (c.3710G>T) pathogenic?

HSPG2 p.Cys1237Phe (c.3710G>T) is classified Uncertain significance in HSPG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.9492); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with HSPG2 p.Cys1237Phe (c.3710G>T)?

HSPG2 p.Cys1237Phe (c.3710G>T) is associated with Inborn genetic diseases (ClinVar).

How common is HSPG2 p.Cys1237Phe (c.3710G>T) in the general population?

HSPG2 p.Cys1237Phe (c.3710G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HSPG2 p.Cys1237Phe (c.3710G>T)?

AlphaMissense predicts likely pathogenic (score 0.9492) — an in-silico prediction, not a clinical call.

HSPG2 p.Cys1237Phe

c.3710G>T · VCV4272750

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9492 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,605,030)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9492	likely pathogenic · top 8% in HSPG2
REVEL	0.956	strongly pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 114 kb · p 1.4e-21 · regional, not allelic
Overall
CADD	28.3	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,605,030). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HSPG2
Protein: p.Cys1237Phe
Coding: c.3710G>T
MANE Select: NM_005529
Type: single nucleotide variant
Location: chr1:21873958 (GRCh38)
Gene constraint: LOEUF 0.603 · pLI <0.01 (gnomAD)
Residue 1237: a disulfide bond; the laminin egf-like 7 domain

Full HSPG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HSPG2 c.3529-3C>T Uncertain significance ★★ same condition
HSPG2 c.9709+3G>A Uncertain significance ★★ same condition
HSPG2 p.Ala1250Thr Uncertain significance ★★ same condition
HSPG2 p.Ala1290Thr Uncertain significance ★★ ⚠ same condition
HSPG2 p.Ala1446Ser Uncertain significance ★★ ⚠ same condition
HSPG2 p.Ala1514Thr Uncertain significance ★★ same condition
HSPG2 p.Ala1524Thr Uncertain significance ★★ same condition
HSPG2 p.Ala1578Val Uncertain significance ★★ ⚠ same condition

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/hspg2-p-cys1237phe (accessed [today's date]).

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