Is CADPS2 p.Arg280Trp (c.838C>T) pathogenic?

CADPS2 p.Arg280Trp (c.838C>T) is classified Uncertain significance in CADPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-01). AlphaMissense: likely pathogenic (0.7718); Ultra-rare (popmax 0.0115%, nfe).

How common is CADPS2 p.Arg280Trp (c.838C>T) in the general population?

CADPS2 p.Arg280Trp (c.838C>T) is ultra-rare (popmax 0.0115%, nfe) (gnomAD).

What do computational predictors say about CADPS2 p.Arg280Trp (c.838C>T)?

AlphaMissense predicts likely pathogenic (score 0.7718) — an in-silico prediction, not a clinical call.

CADPS2 p.Arg280Trp

c.838C>T · VCV3262931

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7718 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0115%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7718	likely pathogenic
REVEL	0.504	indeterminate
SaProt	LLR -9.15	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 566 kb · p 0.00023 · regional, not allelic
Overall
CADD	27.6	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 0.0115% European (non-Finnish) · 136/1,177,712 alleles

Filtering AF 0.00996% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00933%

Overall 0.00882% 142/1,609,450 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0115%	8,660
Remaining individualsnot grpmax-eligible	0.00642%	15,565
African / African-American	0.00134%	74,782
South Asian	0.00111%	90,278

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: CADPS2
Protein: p.Arg280Trp
Coding: c.838C>T
MANE Select: NM_017954
Type: single nucleotide variant
Location: chr7:122629277 (GRCh38)
Gene constraint: LOEUF 0.699 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 79.91

Full CADPS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPS2 p.Thr280Ala Uncertain significance ★ ⚠ same residue
CADPS2 c.3718-15A>C Benign ★★ same type
CADPS2 p.Ala298Thr Benign ★★ same type
CADPS2 p.Asp1088Asn Likely benign ★★ same type
CADPS2 p.Glu1010Lys Benign ★★ same type
CADPS2 p.Leu154= Likely benign ★★ same type
CADPS2 p.Lys338= Benign ★★ same type
CADPS2 p.Met828Val Benign ★★ ⚠ 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/cadps2-p-arg280trp (accessed [today's date]).

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