Is SEC63 p.Asp707Glu (c.2121T>G) pathogenic?

SEC63 p.Asp707Glu (c.2121T>G) is classified Uncertain significance in SEC63 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-05). AlphaMissense: likely pathogenic (0.8924); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SEC63 p.Asp707Glu (c.2121T>G)?

SEC63 p.Asp707Glu (c.2121T>G) is associated with Inborn genetic diseases (ClinVar).

How common is SEC63 p.Asp707Glu (c.2121T>G) in the general population?

SEC63 p.Asp707Glu (c.2121T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SEC63 p.Asp707Glu (c.2121T>G)?

AlphaMissense predicts likely pathogenic (score 0.8924) — an in-silico prediction, not a clinical call.

SEC63 p.Asp707Glu

c.2121T>G · rs2481964973 · VCV2556981

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8924 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8924	likely pathogenic
REVEL	0.548	indeterminate
SaProt	LLR -10.00	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 4,907 bp · p 0.0037 · regional, not allelic
Overall
CADD	22.4	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.Asp707Glu
Coding: c.2121T>G
MANE Select: NM_007214
dbSNP: rs2481964973
Type: single nucleotide variant
Location: chr6:107872826 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 707: 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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SEC63 p.Ala497Thr Uncertain significance ★★ ⚠ same condition
SEC63 p.Arg98Gln Uncertain significance ★★ ⚠ same condition
SEC63 p.Asn349Asp Uncertain significance ★★ ⚠ same condition
SEC63 p.His389Leu Uncertain significance ★★ same condition
SEC63 p.His717Arg Uncertain significance ★★ ⚠ same condition
SEC63 p.Leu191Pro Uncertain significance ★★ ⚠ same condition
SEC63 p.Leu532Phe Uncertain significance ★★ ⚠ same condition
SEC63 p.Lys328Met 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-asp707glu (accessed [today's date]).

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