Is CACNA1D p.Val985Phe (c.2953G>T) pathogenic?

CACNA1D p.Val985Phe (c.2953G>T) is classified Uncertain significance in CACNA1D (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-30). AlphaMissense: likely pathogenic (0.9554); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with CACNA1D p.Val985Phe (c.2953G>T)?

CACNA1D p.Val985Phe (c.2953G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CACNA1D p.Val985Phe (c.2953G>T) in the general population?

CACNA1D p.Val985Phe (c.2953G>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CACNA1D p.Val985Phe (c.2953G>T)?

AlphaMissense predicts likely pathogenic (score 0.9554) — an in-silico prediction, not a clinical call.

CACNA1D p.Val985Phe

c.2953G>T · rs776649485 · VCV1509352

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9554 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9554	likely pathogenic
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -8.41	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 17 kb · p 7e-14 · regional, not allelic
Overall
CADD	32.0	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 0.005% Admixed American · 3/60,024 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000206% 3/1,458,268 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: CACNA1D
Protein: p.Val985Phe
Coding: c.2953G>T
MANE Select: NM_001128840
dbSNP: rs776649485
Type: single nucleotide variant
Location: chr3:53744774 (GRCh38)
Gene constraint: LOEUF 0.253 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.60 · 6 PDB
Residue 985: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CACNA1D p.Val985Ile Uncertain significance ★★ ⚠ same residue
CACNA1D p.Val985= Likely benign ★ same residue
CACNA1D c.377+1G>A Uncertain significance ★★ same condition
CACNA1D c.3915+1G>T Uncertain significance ★★ same condition
CACNA1D p.Ala1179Thr Uncertain significance ★★ ⚠ same condition
CACNA1D p.Ala1527Val Uncertain significance ★★ ⚠ same condition
CACNA1D p.Ala1633Val Uncertain significance ★★ ⚠ same condition
CACNA1D p.Ala1642Val 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-val985phe (accessed [today's date]).

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