Is CCM2L p.Ala93Ser (c.277G>T) pathogenic?

CCM2L p.Ala93Ser (c.277G>T) is classified Uncertain significance in CCM2L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.5967); Absent from gnomAD v4.1.

How common is CCM2L p.Ala93Ser (c.277G>T) in the general population?

CCM2L p.Ala93Ser (c.277G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCM2L p.Ala93Ser (c.277G>T)?

AlphaMissense predicts likely pathogenic (score 0.5967) — an in-silico prediction, not a clinical call.

CCM2L p.Ala93Ser

c.277G>T · VCV4221963

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5967 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5967	likely pathogenic
REVEL	0.26	benign-leaning
SaProt	LLR -7.80	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 21 kb · p 8.3e-05 · regional, not allelic
Overall
CADD	28.7	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

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: CCM2L
Protein: p.Ala93Ser
Coding: c.277G>T
MANE Select: NM_001365692
Type: single nucleotide variant
Location: chr20:32017878 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.84

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.Arg195Cys Uncertain significance ★ ⚠ same type
CCM2L p.Arg204Gln Uncertain significance ★ ⚠ same type
CCM2L p.Arg215Trp Uncertain significance ★ ⚠ same type
CCM2L p.Arg26Cys 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-ala93ser (accessed [today's date]).

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