Is SEC63 p.Arg98Gln (c.293G>A) pathogenic?

SEC63 p.Arg98Gln (c.293G>A) is classified Uncertain significance in SEC63 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-17). AlphaMissense: likely benign (0.2212); Ultra-rare (popmax 0.0134%, eas); Associated with Inborn genetic diseases.

What condition is associated with SEC63 p.Arg98Gln (c.293G>A)?

SEC63 p.Arg98Gln (c.293G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SEC63 p.Arg98Gln (c.293G>A) in the general population?

SEC63 p.Arg98Gln (c.293G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about SEC63 p.Arg98Gln (c.293G>A)?

AlphaMissense predicts likely benign (score 0.2212) — an in-silico prediction, not a clinical call.

SEC63 p.Arg98Gln

c.293G>A · rs746736458 · VCV2490815

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2212 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2212	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -5.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
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 0.84	unconstrained · MANE · 36 kb · p 0.034 · regional, not allelic
Overall
CADD	24.1	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 0.0134% East Asian · 6/44,754 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00395%

Overall 0.000751% 12/1,598,614 alleles · ultra-rare exomes 10/1,446,514 · genomes 2/152,100 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,459
African / African-American	0.00402%	24,850
European (non-Finnish)	0.000257%	388,742

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.Arg98Gln
Coding: c.293G>A
MANE Select: NM_007214
dbSNP: rs746736458
Type: single nucleotide variant
Location: chr6:107924864 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 98: 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.Arg98Ter Pathogenic/Likely pathogenic ★★ same residue
SEC63 p.Ala497Thr 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-arg98gln (accessed [today's date]).

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