Is GPC4 p.Ala519Ser (c.1555G>T) pathogenic?

GPC4 p.Ala519Ser (c.1555G>T) is classified Uncertain significance in GPC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-27). AlphaMissense: likely benign (0.0705); Very rare (popmax 0.000335%, nfe).

How common is GPC4 p.Ala519Ser (c.1555G>T) in the general population?

GPC4 p.Ala519Ser (c.1555G>T) is very rare (popmax 0.000335%, nfe) (gnomAD).

What do computational predictors say about GPC4 p.Ala519Ser (c.1555G>T)?

AlphaMissense predicts likely benign (score 0.0705) — an in-silico prediction, not a clinical call.

GPC4 p.Ala519Ser

c.1555G>T · rs2520390174 · VCV1704775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0705 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000335%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0705	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -5.57	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 0.51	GERP -3.1, phastCons 0.008
Regional constraint	o/e 0.90	unconstrained · MANE · 1,902 bp · p 0.29 · regional, not allelic
Overall
CADD	0.124	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 0.000335% European (non-Finnish) · 3/895,396 alleles

Filtering AF 8.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000248% 3/1,211,540 alleles · very rare exomes 3/1,098,091 · genomes 0/113,449 · 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.Ala519Ser
Coding: c.1555G>T
MANE Select: NM_001448
dbSNP: rs2520390174
Type: single nucleotide variant
Location: chrX:133302983 (GRCh38)
Structure: AlphaFold pLDDT 83.68
Residue 519: a UniProt-annotated variant site (in kpts; increased proteasomal degradation)

Full GPC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GPC4 p.Gln506Ter Pathogenic ★★ same type
GPC4 p.Ala217Val Uncertain significance ★★ ⚠ same type
GPC4 p.Arg219His Uncertain significance ★★ ⚠ same type
GPC4 p.Asn514Ser Uncertain significance ★★ ⚠ same type
GPC4 p.Asn92Ser Uncertain significance ★★ ⚠ same type
GPC4 p.Lys26Glu Uncertain significance ★★ ⚠ same type
GPC4 p.Pro343Leu Uncertain significance ★★ ⚠ same type
GPC4 c.160+96A>G Benign ★★ 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/gpc4-p-ala519ser (accessed [today's date]).

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