Is CACNA1D p.Phe303Ser (c.908T>C) pathogenic?

CACNA1D p.Phe303Ser (c.908T>C) is classified Uncertain significance in CACNA1D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-24). AlphaMissense: likely benign (0.2567); Absent from gnomAD v4.1; Associated with CACNA1D-related neurodevelopmental and endocrine disorders.

What condition is associated with CACNA1D p.Phe303Ser (c.908T>C)?

CACNA1D p.Phe303Ser (c.908T>C) is associated with CACNA1D-related neurodevelopmental and endocrine disorders (ClinVar).

How common is CACNA1D p.Phe303Ser (c.908T>C) in the general population?

CACNA1D p.Phe303Ser (c.908T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CACNA1D p.Phe303Ser (c.908T>C)?

AlphaMissense predicts likely benign (score 0.2567) — an in-silico prediction, not a clinical call.

CACNA1D p.Phe303Ser

c.908T>C · rs2094255562 · VCV989279

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2567 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CACNA1D-related neurodevelopmental and endocrine disorders

Computational evidence

Protein change
AlphaMissense	0.2567	likely benign
REVEL	0.598	indeterminate
SaProt	LLR -9.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 201 kb · p 1.3e-24 · regional, not allelic
Overall
CADD	25.4	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: CACNA1D
Protein: p.Phe303Ser
Coding: c.908T>C
MANE Select: NM_001128840
dbSNP: rs2094255562
Type: single nucleotide variant
Location: chr3:53665801 (GRCh38)
Gene constraint: LOEUF 0.253 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.60 · 6 PDB
Residue 303: a β-strand

Full CACNA1D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CACNA1D-related neurodevelopmental and endocrine disorders

Similar variants

CACNA1D p.Ala501Val Uncertain significance ★★ same condition
CACNA1D p.Arg1173His Uncertain significance ★★ ⚠ same condition
CACNA1D p.Arg844Cys Uncertain significance ★★ ⚠ same condition
CACNA1D p.Asn785Ser Uncertain significance ★★ ⚠ same condition
CACNA1D p.Met647Leu Uncertain significance ★★ same condition
CACNA1D p.Pro1897Ala Uncertain significance ★★ ⚠ same condition
CACNA1D p.Asp421Gly Uncertain significance ★ ⚠ same condition
CACNA1D p.Asp449Asn Uncertain significance ★ ⚠ same condition

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/cacna1d-p-phe303ser (accessed [today's date]).

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