Is CADPS2 p.Val596Phe (c.1786G>T) pathogenic?

CADPS2 p.Val596Phe (c.1786G>T) is classified Uncertain significance in CADPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-10). AlphaMissense: likely benign (0.1892); Ultra-rare (popmax 0.0165%, mid).

How common is CADPS2 p.Val596Phe (c.1786G>T) in the general population?

CADPS2 p.Val596Phe (c.1786G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CADPS2 p.Val596Phe (c.1786G>T)?

AlphaMissense predicts likely benign (score 0.1892) — an in-silico prediction, not a clinical call.

CADPS2 p.Val596Phe

c.1786G>T · VCV3262929

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1892 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1892	likely benign
REVEL	0.161	moderately benign-leaning
SaProt	LLR -12.01	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.6	GERP -5.9
Regional constraint	o/e 0.91	unconstrained · MANE · 566 kb · p 0.00023 · regional, not allelic
Overall
CADD	14.44	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 · 1/6,078 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00316% 51/1,613,346 alleles · ultra-rare exomes 50/1,461,276 · genomes 1/152,070 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
Admixed American	0.00667%	14,993
European (non-Finnish)	0.00365%	27,432
South Asian	0.0022%	45,541
Remaining individualsnot grpmax-eligible	0.0016%	62,442

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.Val596Phe
Coding: c.1786G>T
MANE Select: NM_017954
Type: single nucleotide variant
Location: chr7:122490147 (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

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
CADPS2 p.Thr819= 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-val596phe (accessed [today's date]).

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