Is CASS4 p.Pro104Arg (c.311C>G) pathogenic?

CASS4 p.Pro104Arg (c.311C>G) is classified Uncertain significance in CASS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-02). AlphaMissense: likely benign (0.085); Absent from gnomAD v4.1.

How common is CASS4 p.Pro104Arg (c.311C>G) in the general population?

CASS4 p.Pro104Arg (c.311C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CASS4 p.Pro104Arg (c.311C>G)?

AlphaMissense predicts likely benign (score 0.085) — an in-silico prediction, not a clinical call.

CASS4 p.Pro104Arg

c.311C>G · VCV4648541

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.085 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.085	likely benign
REVEL	0.01	strongly benign-leaning
SaProt	LLR -7.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.24	donor loss · deltas
Constraint at this position
Conservation	phyloP 0.005	GERP -1.7
Regional constraint	o/e 0.87	unconstrained · MANE · 46 kb · p 2.4e-05 · regional, not allelic
Overall
CADD	3.879	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CASS4
Protein: p.Pro104Arg
Coding: c.311C>G
MANE Select: NM_020356
Type: single nucleotide variant
Location: chr20:56437438 (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-pro104arg (accessed [today's date]).

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