Is CACNA1D p.Met1237Val (c.3709A>G) pathogenic?

CACNA1D p.Met1237Val (c.3709A>G) is classified Uncertain significance in CACNA1D (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-24). AlphaMissense: likely pathogenic (0.713); Very rare (popmax 0.00568%, nfe).

How common is CACNA1D p.Met1237Val (c.3709A>G) in the general population?

CACNA1D p.Met1237Val (c.3709A>G) is very rare (popmax 0.00568%, nfe) (gnomAD).

What do computational predictors say about CACNA1D p.Met1237Val (c.3709A>G)?

AlphaMissense predicts likely pathogenic (score 0.713) — an in-silico prediction, not a clinical call.

CACNA1D p.Met1237Val

c.3709A>G · rs767083533 · VCV517201

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.713 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00568%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.713	likely pathogenic
REVEL	0.859	moderately pathogenic-leaning
SaProt	LLR -7.68	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.8, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 25 kb · p 2.1e-09 · regional, not allelic
Overall
CADD	25.1	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 0.00568% European (non-Finnish) · 67/1,178,986 alleles

Filtering AF 0.00454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00417%

Overall 0.00459% 67/1,460,732 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.Met1237Val
Coding: c.3709A>G
MANE Select: NM_001128840
dbSNP: rs767083533
Type: single nucleotide variant
Location: chr3:53753605 (GRCh38)
Gene constraint: LOEUF 0.253 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.60 · 6 PDB
Residue 1237: an α-helix

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

Similar variants

CACNA1D p.Met1237Leu Uncertain significance ★★ ⚠ same residue
CACNA1D p.Ser652Leu Pathogenic/Likely pathogenic ★★ same type
CACNA1D c.1892+3A>G Uncertain significance ★★ same type
CACNA1D c.2406+3A>G Uncertain significance ★★ same type
CACNA1D c.2474-1G>A Uncertain significance ★★ same type
CACNA1D c.2474-2A>C Uncertain significance ★★ same type
CACNA1D c.2751+2T>C Uncertain significance ★★ same type
CACNA1D c.3314+1G>A 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/cacna1d-p-met1237val (accessed [today's date]).

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