Is SEC63 p.Glu645Lys (c.1933G>A) pathogenic?

SEC63 p.Glu645Lys (c.1933G>A) is classified Uncertain significance in SEC63 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: ambiguous (0.5197); Very rare (popmax 0.000125%).

How common is SEC63 p.Glu645Lys (c.1933G>A) in the general population?

SEC63 p.Glu645Lys (c.1933G>A) is very rare (popmax 0.000125%) (gnomAD).

What do computational predictors say about SEC63 p.Glu645Lys (c.1933G>A)?

AlphaMissense predicts ambiguous (score 0.5197) — an in-silico prediction, not a clinical call.

SEC63 p.Glu645Lys

c.1933G>A · VCV4737272

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5197 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000125%)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5197	ambiguous
REVEL	0.173	moderately benign-leaning
SaProt	LLR -7.87	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 37 kb · p 6.7e-08 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.000125%

Overall 0.000125% 2/1,599,838 alleles · very rare exomes 1/1,447,694 · genomes 1/152,144 · joint denominator

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.Glu645Lys
Coding: c.1933G>A
MANE Select: NM_007214
Type: single nucleotide variant
Location: chr6:107881151 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 645: the sec63 2 domain; a UniProt-annotated variant site (in pcld2)

Full SEC63 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SEC63 c.452+1G>A Pathogenic/Likely pathogenic ★★ same type
SEC63 c.625-2A>G Likely pathogenic ★★ same type
SEC63 c.733+1G>A Pathogenic ★★ same type
SEC63 p.Arg239Ter Pathogenic/Likely pathogenic ★★ same type
SEC63 p.Arg622Ter Pathogenic/Likely pathogenic ★★ same type
SEC63 p.Arg98Ter Pathogenic/Likely pathogenic ★★ same type
SEC63 p.Ser632Ter Pathogenic/Likely pathogenic ★★ same type
SEC63 p.Trp58Ter Pathogenic ★★ same type

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-glu645lys (accessed [today's date]).

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