Is SEC63 p.Ser526Ter (c.1577C>A) pathogenic?

SEC63 p.Ser526Ter (c.1577C>A) is classified Pathogenic in SEC63 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-09-01). Very rare (popmax 0.00182%, amr); Associated with autosomal dominant polycystic liver disease.

What condition is associated with SEC63 p.Ser526Ter (c.1577C>A)?

SEC63 p.Ser526Ter (c.1577C>A) is associated with autosomal dominant polycystic liver disease (ClinVar).

How common is SEC63 p.Ser526Ter (c.1577C>A) in the general population?

SEC63 p.Ser526Ter (c.1577C>A) is very rare (popmax 0.00182%, amr) (gnomAD).

SEC63 p.Ser526Ter

c.1577C>A · rs779331877 · VCV1255599

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00182%, amr)

Conditions

autosomal dominant polycystic liver disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 16 of 21
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00182% Admixed American · 1/54,864 alleles

Overall 0.000126% 2/1,590,614 alleles · very rare exomes 2/1,440,894 · genomes 0/149,720 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00182%	54,864
European (non-Finnish)	8.53e-05%	1,172,904

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.Ser526Ter
Coding: c.1577C>A
MANE Select: NM_007214
dbSNP: rs779331877
Type: single nucleotide variant
Location: chr6:107893579 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 526: the 'disordered' region; a UniProt-annotated variant site (in pcld2); the sec63 1 domain

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

Disease context

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

Similar variants

SEC63 p.Arg239Ter Pathogenic/Likely pathogenic ★★ same condition
SEC63 p.Arg622Ter Pathogenic/Likely pathogenic ★★ same condition
SEC63 p.Arg98Ter Pathogenic/Likely pathogenic ★★ same condition
SEC63 p.Ser632Ter Pathogenic/Likely pathogenic ★★ same condition
SEC63 p.Trp58Ter Pathogenic ★★ same condition
SEC63 p.Arg45Ter Pathogenic ★ same condition
SEC63 p.Ile216Val Uncertain significance ★ same condition
SEC63 p.Thr676Ala 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/sec63-p-ser526ter (accessed [today's date]).

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