Is SEC63 p.Gln375Pro (c.1124A>C) pathogenic?

SEC63 p.Gln375Pro (c.1124A>C) is classified Likely pathogenic in SEC63 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely pathogenic (0.9811); Absent from gnomAD v4.1; Associated with autosomal dominant polycystic liver disease.

What condition is associated with SEC63 p.Gln375Pro (c.1124A>C)?

SEC63 p.Gln375Pro (c.1124A>C) is associated with autosomal dominant polycystic liver disease (ClinVar).

How common is SEC63 p.Gln375Pro (c.1124A>C) in the general population?

SEC63 p.Gln375Pro (c.1124A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SEC63 p.Gln375Pro (c.1124A>C)?

AlphaMissense predicts likely pathogenic (score 0.9811) — an in-silico prediction, not a clinical call.

SEC63 p.Gln375Pro

c.1124A>C · rs1787041288 · VCV1255629

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9811 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant polycystic liver disease

Computational evidence

Protein change
AlphaMissense	0.9811	likely pathogenic ✓ concordant with ClinVar
REVEL	0.864	moderately pathogenic-leaning
SaProt	LLR -10.49	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 37 kb · p 6.7e-08 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SEC63
Protein: p.Gln375Pro
Coding: c.1124A>C
MANE Select: NM_007214
dbSNP: rs1787041288
Type: single nucleotide variant
Location: chr6:107902929 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 375: 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.Gln375Arg Likely pathogenic ⚠ same residue
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

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-gln375pro (accessed [today's date]).

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