Is SEC63 p.Asp393Val (c.1178A>T) pathogenic?

SEC63 p.Asp393Val (c.1178A>T) is classified Uncertain significance in SEC63 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-21). AlphaMissense: likely pathogenic (0.6242); Ultra-rare (popmax 0.0165%, mid).

How common is SEC63 p.Asp393Val (c.1178A>T) in the general population?

SEC63 p.Asp393Val (c.1178A>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about SEC63 p.Asp393Val (c.1178A>T)?

AlphaMissense predicts likely pathogenic (score 0.6242) — an in-silico prediction, not a clinical call.

SEC63 p.Asp393Val

c.1178A>T · rs200071267 · VCV1929745

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6242 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6242	likely pathogenic
REVEL	0.408	indeterminate
SaProt	LLR -7.42	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 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	29.0	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000682% 11/1,614,004 alleles · ultra-rare exomes 9/1,461,728 · genomes 2/152,276 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.0107%	9,377
Remaining individualsnot grpmax-eligible	0.0032%	31,251

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.Asp393Val
Coding: c.1178A>T
MANE Select: NM_007214
dbSNP: rs200071267
Type: single nucleotide variant
Location: chr6:107902875 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 393: 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

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-asp393val (accessed [today's date]).

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