Is CADPS2 p.Val374Ala (c.1121T>C) pathogenic?

CADPS2 p.Val374Ala (c.1121T>C) is classified Uncertain significance in CADPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-12). AlphaMissense: likely pathogenic (0.8966); Very rare (popmax 8.76e-05%, nfe).

How common is CADPS2 p.Val374Ala (c.1121T>C) in the general population?

CADPS2 p.Val374Ala (c.1121T>C) is very rare (popmax 8.76e-05%, nfe) (gnomAD).

What do computational predictors say about CADPS2 p.Val374Ala (c.1121T>C)?

AlphaMissense predicts likely pathogenic (score 0.8966) — an in-silico prediction, not a clinical call.

CADPS2 p.Val374Ala

c.1121T>C · VCV4218203

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8966 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.76e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8966	likely pathogenic
REVEL	0.55	indeterminate
SaProt	LLR -11.34	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 566 kb · p 0.00023 · regional, not allelic
Overall
CADD	24.7	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 8.76e-05% European (non-Finnish) · 1/1,140,978 alleles

Overall 7.18e-05% 1/1,393,226 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.Val374Ala
Coding: c.1121T>C
MANE Select: NM_017954
Type: single nucleotide variant
Location: chr7:122615283 (GRCh38)
Gene constraint: LOEUF 0.699 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 79.91
Residue 374: the dm10 domain; the c2 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-val374ala (accessed [today's date]).

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