Is SEC63 p.Thr73= (c.219A>G) pathogenic?

SEC63 p.Thr73= (c.219A>G) is classified Uncertain significance in SEC63 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-23). Very rare (popmax 0.00181%, nfe); Associated with polycystic liver disease 2.

What condition is associated with SEC63 p.Thr73= (c.219A>G)?

SEC63 p.Thr73= (c.219A>G) is associated with polycystic liver disease 2 (ClinVar).

How common is SEC63 p.Thr73= (c.219A>G) in the general population?

SEC63 p.Thr73= (c.219A>G) is very rare (popmax 0.00181%, nfe) (gnomAD).

SEC63 p.Thr73=

c.219A>G · VCV3592928

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00181%, nfe)

Conditions

polycystic liver disease 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.47	donor gain · deltas
Constraint at this position
Conservation	phyloP 1.6	GERP -0.93, phastCons 1
Overall
CADD	17.75	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00181% European (non-Finnish) · 20/1,105,704 alleles

Filtering AF 0.00118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00096%

Overall 0.00144% 22/1,532,128 alleles · very rare exomes 21/1,379,890 · genomes 1/152,238 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00181%	55,285
Remaining individualsnot grpmax-eligible	0.00167%	59,862
South Asian	0.00112%	89,274

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: SEC63
Protein: p.Thr73=
Coding: c.219A>G
MANE Select: NM_007214
Type: single nucleotide variant
Location: chr6:107929420 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 73: a UniProt-annotated variant site (in pcld2)

Full SEC63 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

polycystic liver disease 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SEC63 p.Thr73Ile Uncertain significance ★ ⚠ same residue
SEC63 p.Thr73Lys Uncertain significance ★ same residue
SEC63 c.452+1G>A Pathogenic/Likely pathogenic ★★ same condition
SEC63 c.625-2A>G Likely pathogenic ★★ same condition
SEC63 c.733+1G>A Pathogenic ★★ same condition
SEC63 p.Arg239Ter Pathogenic/Likely pathogenic ★★ same condition
SEC63 p.Arg622Ter Pathogenic/Likely pathogenic ★★ same condition
SEC63 p.Arg98Ter Pathogenic/Likely pathogenic ★★ 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/sec63-p-thr73 (accessed [today's date]).

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