Is SEC63 p.Phe426= (c.1278C>T) pathogenic?

SEC63 p.Phe426= (c.1278C>T) is classified Benign/Likely benign in SEC63 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-23). Low-frequency (popmax 2.99%, sas); Associated with polycystic liver disease 2.

What condition is associated with SEC63 p.Phe426= (c.1278C>T)?

SEC63 p.Phe426= (c.1278C>T) is associated with polycystic liver disease 2 (ClinVar).

How common is SEC63 p.Phe426= (c.1278C>T) in the general population?

SEC63 p.Phe426= (c.1278C>T) is low-frequency (popmax 2.99%, sas) (gnomAD).

SEC63 p.Phe426=

c.1278C>T · rs146559698 · VCV354905

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.99%, sas)

Conditions

polycystic liver disease 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.9	GERP 1, phastCons 1
Overall
CADD	10.14	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.99% South Asian · 2,718/91,022 alleles

Filtering AF 2.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.85%

Overall 0.245% 3,950/1,611,738 alleles · low-frequency exomes 3,688/1,459,778 · genomes 262/151,960 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	2.99%	33
Ashkenazi Jewishnot grpmax-eligible	1.31%	77
Middle Eastern	0.43%	232
Remaining individualsnot grpmax-eligible	0.324%	309
Admixed American	0.0617%	1,621
European (non-Finnish)	0.0479%	2,089
African / African-American	0.0147%	6,804
Finnishnot grpmax-eligible	0.00782%	12,787
East Asian	0.00223%	44,768

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.Phe426=
Coding: c.1278C>T
MANE Select: NM_007214
dbSNP: rs146559698
Type: single nucleotide variant
Location: chr6:107901449 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 426: 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 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
SEC63 p.Ser632Ter Pathogenic/Likely pathogenic ★★ same condition
SEC63 c.452+3A>G 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-phe426 (accessed [today's date]).

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