Is SEC63 p.Arg356His (c.1067G>A) pathogenic?

SEC63 p.Arg356His (c.1067G>A) is classified Uncertain significance in SEC63 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-28). AlphaMissense: likely benign (0.1209); Ultra-rare (popmax 0.0164%, mid); Associated with polycystic liver disease 2.

What condition is associated with SEC63 p.Arg356His (c.1067G>A)?

SEC63 p.Arg356His (c.1067G>A) is associated with polycystic liver disease 2 (ClinVar).

How common is SEC63 p.Arg356His (c.1067G>A) in the general population?

SEC63 p.Arg356His (c.1067G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about SEC63 p.Arg356His (c.1067G>A)?

AlphaMissense predicts likely benign (score 0.1209) — an in-silico prediction, not a clinical call.

SEC63 p.Arg356His

c.1067G>A · VCV3592908

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1209 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

polycystic liver disease 2

Computational evidence

Protein change
AlphaMissense	0.1209	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -6.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.32	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 37 kb · p 6.7e-08 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00149% 24/1,613,738 alleles · ultra-rare exomes 23/1,461,796 · genomes 1/151,942 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00334%	29,978
European (non-Finnish)	0.00169%	58,999
African / African-American	0.00134%	74,828

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.Arg356His
Coding: c.1067G>A
MANE Select: NM_007214
Type: single nucleotide variant
Location: chr6:107902986 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 356: 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.Arg356Cys 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-arg356his (accessed [today's date]).

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