Is SEC63 p.Arg62Trp (c.184C>T) pathogenic?

SEC63 p.Arg62Trp (c.184C>T) is classified Uncertain significance in SEC63 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-17). AlphaMissense: likely pathogenic (0.6492); Ultra-rare (popmax 0.0121%, sas).

How common is SEC63 p.Arg62Trp (c.184C>T) in the general population?

SEC63 p.Arg62Trp (c.184C>T) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about SEC63 p.Arg62Trp (c.184C>T)?

AlphaMissense predicts likely pathogenic (score 0.6492) — an in-silico prediction, not a clinical call.

SEC63 p.Arg62Trp

c.184C>T · rs765786241 · VCV2186340

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6492 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6492	likely pathogenic
REVEL	0.535	indeterminate
SaProt	LLR -11.22	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.1	GERP -0.34, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 0.034 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0121% South Asian · 11/90,788 alleles

Filtering AF 0.00678% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00523%

Overall 0.00394% 63/1,600,532 alleles · ultra-rare exomes 60/1,448,352 · genomes 3/152,180 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,253
Remaining individualsnot grpmax-eligible	0.00484%	20,677
European (non-Finnish)	0.00411%	24,332
Admixed American	0.00167%	59,962

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.Arg62Trp
Coding: c.184C>T
MANE Select: NM_007214
dbSNP: rs765786241
Type: single nucleotide variant
Location: chr6:107929455 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.91 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.71
Residue 62: 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-arg62trp (accessed [today's date]).

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