Is SEC63 p.Arg397Gln (c.1190G>A) pathogenic?

SEC63 p.Arg397Gln (c.1190G>A) is classified Uncertain significance in SEC63 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). AlphaMissense: ambiguous (0.532); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with SEC63 p.Arg397Gln (c.1190G>A)?

SEC63 p.Arg397Gln (c.1190G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SEC63 p.Arg397Gln (c.1190G>A) in the general population?

SEC63 p.Arg397Gln (c.1190G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about SEC63 p.Arg397Gln (c.1190G>A)?

AlphaMissense predicts ambiguous (score 0.532) — an in-silico prediction, not a clinical call.

SEC63 p.Arg397Gln

c.1190G>A · rs1787039111 · VCV2508991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.532 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.532	ambiguous
REVEL	0.179	moderately benign-leaning
SaProt	LLR -5.13	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 1.4, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 37 kb · p 6.7e-08 · regional, not allelic
Overall
CADD	26.0	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 0.00267% African / African-American · 2/74,868 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000682% 11/1,613,754 alleles · very rare exomes 9/1,461,690 · genomes 2/152,064 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,826
African / African-Americangrpmax	0.00267%	37,434
Admixed American	0.00167%	59,978
European (non-Finnish)	0.000424%	235,978

Remaining individuals 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.Arg397Gln
Coding: c.1190G>A
MANE Select: NM_007214
dbSNP: rs1787039111
Type: single nucleotide variant
Location: chr6:107902863 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 397: 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

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

Similar variants

SEC63 p.Arg397Trp Uncertain significance ★ same residue
SEC63 p.Arg397= Likely benign ★ same residue
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

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-arg397gln (accessed [today's date]).

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