Is SEC63 p.Ala151Val (c.452C>T) pathogenic?

SEC63 p.Ala151Val (c.452C>T) is classified Uncertain significance in SEC63 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-17). AlphaMissense: likely pathogenic (0.9132); Very rare (popmax 0.00135%, afr); Associated with polycystic liver disease 2.

What condition is associated with SEC63 p.Ala151Val (c.452C>T)?

SEC63 p.Ala151Val (c.452C>T) is associated with polycystic liver disease 2 (ClinVar).

How common is SEC63 p.Ala151Val (c.452C>T) in the general population?

SEC63 p.Ala151Val (c.452C>T) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about SEC63 p.Ala151Val (c.452C>T)?

AlphaMissense predicts likely pathogenic (score 0.9132) — an in-silico prediction, not a clinical call.

SEC63 p.Ala151Val

c.452C>T · rs1360860173 · VCV905039

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9132 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

polycystic liver disease 2

Computational evidence

Protein change
AlphaMissense	0.9132	likely pathogenic
REVEL	0.293	indeterminate
SaProt	LLR -10.85	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 8,460 bp · p 2.5e-06 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00135% African / African-American · 1/73,818 alleles

Filtering AF 0.000371% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000269%

Overall 0.000764% 12/1,569,824 alleles · very rare exomes 10/1,417,956 · genomes 2/151,868 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00313%	31,935
African / African-Americangrpmax	0.00135%	73,818
European (non-Finnish)	0.000789%	126,678

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala151Val
Coding: c.452C>T
MANE Select: NM_007214
dbSNP: rs1360860173
Type: single nucleotide variant
Location: chr6:107921797 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 151: a UniProt-annotated variant site (in pcld2); the j 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.Ala151Thr 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
SEC63 p.Ser632Ter 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-ala151val (accessed [today's date]).

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