Is GPC4 p.Pro343Ser (c.1027C>T) pathogenic?

GPC4 p.Pro343Ser (c.1027C>T) is classified Uncertain significance in GPC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely benign (0.0645); Very rare (popmax 0.00218%, amr); Associated with Inborn genetic diseases.

What condition is associated with GPC4 p.Pro343Ser (c.1027C>T)?

GPC4 p.Pro343Ser (c.1027C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GPC4 p.Pro343Ser (c.1027C>T) in the general population?

GPC4 p.Pro343Ser (c.1027C>T) is very rare (popmax 0.00218%, amr) (gnomAD).

What do computational predictors say about GPC4 p.Pro343Ser (c.1027C>T)?

AlphaMissense predicts likely benign (score 0.0645) — an in-silico prediction, not a clinical call.

GPC4 p.Pro343Ser

c.1027C>T · VCV4265495

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0645 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00218%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0645	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR 0.55	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 5.2	GERP -0.084, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 34 kb · p 6.9e-12 · regional, not allelic
Overall
CADD	18.02	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 0.00218% Admixed American · 1/45,951 alleles

Overall 8.26e-05% 1/1,211,342 alleles · very rare exomes 1/1,098,052 · genomes 0/113,290 · 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: GPC4
Protein: p.Pro343Ser
Coding: c.1027C>T
MANE Select: NM_001448
Type: single nucleotide variant
Location: chrX:133305900 (GRCh38)
Structure: AlphaFold pLDDT 83.68

Full GPC4 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

GPC4 p.Pro343Leu Uncertain significance ★★ ⚠ same residue
GPC4 p.Asn514Ser Uncertain significance ★★ ⚠ same condition
GPC4 p.Asn92Ser Uncertain significance ★★ ⚠ same condition
GPC4 p.Lys26Glu Uncertain significance ★★ ⚠ same condition
GPC4 p.Ala299Thr Uncertain significance ★ ⚠ same condition
GPC4 p.Ala467Val Uncertain significance ★ ⚠ same condition
GPC4 p.Arg148His Uncertain significance ★ ⚠ same condition
GPC4 p.Arg258Trp 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/gpc4-p-pro343ser (accessed [today's date]).

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