Is SEC63 p.Pro536fs (c.1605dup) pathogenic?

SEC63 p.Pro536fs (c.1605dup) is classified Conflicting classifications of pathogenicity in SEC63 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-29). Rare (popmax 0.135%, amr); Associated with polycystic liver disease 2.

What condition is associated with SEC63 p.Pro536fs (c.1605dup)?

SEC63 p.Pro536fs (c.1605dup) is associated with polycystic liver disease 2 (ClinVar).

How common is SEC63 p.Pro536fs (c.1605dup) in the general population?

SEC63 p.Pro536fs (c.1605dup) is rare (popmax 0.135%, amr) (gnomAD).

SEC63 p.Pro536fs

c.1605dup · rs752868449 · VCV194646

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.135%, amr)

Conditions

polycystic liver disease 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 16 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.35	GERP -1.1, phastCons 0.15
Overall
CADD	25.0	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 0.135% Admixed American · 73/53,924 alleles

Filtering AF 0.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.07% 1,040/1,485,648 alleles · rare exomes 1,034/1,336,780 · genomes 6/148,868 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.135%	739
Finnishnot grpmax-eligible	0.0813%	1,230
Ashkenazi Jewishnot grpmax-eligible	0.0775%	1,290
European (non-Finnish)	0.071%	1,409
South Asian	0.07%	1,428
Remaining individualsnot grpmax-eligible	0.0598%	1,673
African / African-American	0.0327%	3,059
East Asian	0.0241%	4,156
Middle Eastern	0.0181%	5,530

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.Pro536fs
Coding: c.1605dup
MANE Select: NM_007214
dbSNP: rs752868449
Type: Duplication
Location: chr6:107893550 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 536: 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

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

Similar variants

SEC63 p.Val398fs Pathogenic/Likely pathogenic ★★ same condition
SEC63 p.Met1fs Uncertain significance ★★ same condition
SEC63 c.1210-18dup Benign ★★ same condition
SEC63 c.1936-27_1936-25dup Benign/Likely benign ★★ same condition
SEC63 c.340-6_340-4dup Benign ★★ same condition
SEC63 p.Arg98fs Likely pathogenic ★ same condition
SEC63 p.Asn365fs Pathogenic ★ same condition
SEC63 p.Pro443fs 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-pro536fs (accessed [today's date]).

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