Is GPC6 p.Cys554Arg (c.1660T>C) pathogenic?

GPC6 p.Cys554Arg (c.1660T>C) is classified Uncertain significance in GPC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: likely benign (0.0873); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with GPC6 p.Cys554Arg (c.1660T>C)?

GPC6 p.Cys554Arg (c.1660T>C) is associated with Inborn genetic diseases (ClinVar).

How common is GPC6 p.Cys554Arg (c.1660T>C) in the general population?

GPC6 p.Cys554Arg (c.1660T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about GPC6 p.Cys554Arg (c.1660T>C)?

AlphaMissense predicts likely benign (score 0.0873) — an in-silico prediction, not a clinical call.

GPC6 p.Cys554Arg

c.1660T>C · VCV4031216

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0873 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0873	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -5.30	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 0.18	GERP -4.5, phastCons 0.99
Regional constraint	o/e 0.90	unconstrained · MANE · 1,176 kb · p 0.011 · regional, not allelic
Overall
CADD	13.16	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 0.00167% Admixed American · 1/60,006 alleles

Overall 6.2e-05% 1/1,612,416 alleles · very rare exomes 0/1,460,164 · genomes 1/152,252 · 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: GPC6
Protein: p.Cys554Arg
Coding: c.1660T>C
MANE Select: NM_005708
Type: single nucleotide variant
Location: chr13:94403209 (GRCh38)
Gene constraint: LOEUF 0.384 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.67

Full GPC6 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

GPC6 p.Ala232Thr Uncertain significance ★★ same condition
GPC6 p.Ala519Thr Uncertain significance ★★ ⚠ same condition
GPC6 p.Arg110Gln Uncertain significance ★★ ⚠ same condition
GPC6 p.Arg126Trp Uncertain significance ★★ ⚠ same condition
GPC6 p.Arg363His Uncertain significance ★★ same condition
GPC6 p.Arg383Gln Uncertain significance ★★ ⚠ same condition
GPC6 p.Arg468His Uncertain significance ★★ ⚠ same condition
GPC6 p.Arg555Gly 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/gpc6-p-cys554arg (accessed [today's date]).

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