Is CCM2L p.Ser246Asn (c.737G>A) pathogenic?

CCM2L p.Ser246Asn (c.737G>A) is classified Uncertain significance in CCM2L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely pathogenic (0.8189); Very rare (popmax 0.000541%, nfe).

How common is CCM2L p.Ser246Asn (c.737G>A) in the general population?

CCM2L p.Ser246Asn (c.737G>A) is very rare (popmax 0.000541%, nfe) (gnomAD).

What do computational predictors say about CCM2L p.Ser246Asn (c.737G>A)?

AlphaMissense predicts likely pathogenic (score 0.8189) — an in-silico prediction, not a clinical call.

CCM2L p.Ser246Asn

c.737G>A · VCV4649962

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8189 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000541%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8189	likely pathogenic
REVEL	0.17	moderately benign-leaning
SaProt	LLR -11.51	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 21 kb · p 8.3e-05 · regional, not allelic
Overall
CADD	26.4	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 0.000541% European (non-Finnish) · 5/924,990 alleles

Filtering AF 0.000158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000115%

Overall 0.000434% 5/1,152,070 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: CCM2L
Protein: p.Ser246Asn
Coding: c.737G>A
MANE Select: NM_001365692
Type: single nucleotide variant
Location: chr20:32019213 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.84
Residue 246: the 'disordered' region

Full CCM2L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCM2L p.Ala183Glu Uncertain significance ★ ⚠ same type
CCM2L p.Ala214Gly Uncertain significance ★ ⚠ same type
CCM2L p.Ala299Ser Uncertain significance ★ ⚠ same type
CCM2L p.Ala435= Uncertain significance ★ same type
CCM2L p.Ala93Ser Uncertain significance ★ ⚠ same type
CCM2L p.Arg195Cys Uncertain significance ★ ⚠ same type
CCM2L p.Arg204Gln Uncertain significance ★ ⚠ same type
CCM2L p.Arg215Trp 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/ccm2l-p-ser246asn (accessed [today's date]).

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