Is CASS4 p.Ala682Val (c.2045C>T) pathogenic?

CASS4 p.Ala682Val (c.2045C>T) is classified Uncertain significance in CASS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.5976); Very rare (popmax 0.00144%, nfe).

How common is CASS4 p.Ala682Val (c.2045C>T) in the general population?

CASS4 p.Ala682Val (c.2045C>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about CASS4 p.Ala682Val (c.2045C>T)?

AlphaMissense predicts likely pathogenic (score 0.5976) — an in-silico prediction, not a clinical call.

CASS4 p.Ala682Val

c.2045C>T · VCV4648537

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5976 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5976	likely pathogenic
REVEL	0.204	benign-leaning
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 46 kb · p 2.4e-05 · regional, not allelic
Overall
CADD	26.7	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 0.00144% European (non-Finnish) · 17/1,180,048 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00112% 18/1,613,996 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00144%	69,415
African / African-American	0.00134%	74,884

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: CASS4
Protein: p.Ala682Val
Coding: c.2045C>T
MANE Select: NM_020356
Type: single nucleotide variant
Location: chr20:56458431 (GRCh38)
Gene constraint: LOEUF 0.53 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 58.88 · 1 PDB

Full CASS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASS4 p.Arg491Lys Benign ★★ same type
CASS4 p.Leu71= Benign ★★ same type
CASS4 p.Ser426Leu Benign ★★ same type
CASS4 p.Ala10Val Uncertain significance ★ ⚠ same type
CASS4 p.Ala16Asp Uncertain significance ★ ⚠ same type
CASS4 p.Ala271Thr Uncertain significance ★ ⚠ same type
CASS4 p.Ala377Val Uncertain significance ★ ⚠ same type
CASS4 p.Ala456Thr Uncertain significance ★ ⚠ 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/cass4-p-ala682val (accessed [today's date]).

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