Is CADPS2 p.Leu538Val (c.1612C>G) pathogenic?

CADPS2 p.Leu538Val (c.1612C>G) is classified Uncertain significance in CADPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: ambiguous (0.5002); Very rare (popmax 0.00134%, afr).

How common is CADPS2 p.Leu538Val (c.1612C>G) in the general population?

CADPS2 p.Leu538Val (c.1612C>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CADPS2 p.Leu538Val (c.1612C>G)?

AlphaMissense predicts ambiguous (score 0.5002) — an in-silico prediction, not a clinical call.

CADPS2 p.Leu538Val

c.1612C>G · VCV4218210

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5002 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Computational evidence

Protein change
AlphaMissense	0.5002	ambiguous
REVEL	0.618	indeterminate
SaProt	LLR -11.35	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 566 kb · p 0.00023 · 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 0.00134% African / African-American · 1/74,798 alleles

Overall 0.000658% 1/152,044 alleles · very rare

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.Leu538Val
Coding: c.1612C>G
MANE Select: NM_017954
Type: single nucleotide variant
Location: chr7:122491351 (GRCh38)
Gene constraint: LOEUF 0.699 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 79.91
Residue 538: the ph domain

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-leu538val (accessed [today's date]).

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