Is CCM2L p.Asp167Tyr (c.499G>T) pathogenic?

CCM2L p.Asp167Tyr (c.499G>T) is classified Uncertain significance in CCM2L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.2603); Ultra-rare (popmax 0.0155%, nfe).

How common is CCM2L p.Asp167Tyr (c.499G>T) in the general population?

CCM2L p.Asp167Tyr (c.499G>T) is ultra-rare (popmax 0.0155%, nfe) (gnomAD).

What do computational predictors say about CCM2L p.Asp167Tyr (c.499G>T)?

AlphaMissense predicts likely benign (score 0.2603) — an in-silico prediction, not a clinical call.

CCM2L p.Asp167Tyr

c.499G>T · VCV4221965

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2603 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0155%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2603	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -7.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 0.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 21 kb · p 8.3e-05 · regional, not allelic
Overall
CADD	23.5	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

Grpmax group 0.0155% European (non-Finnish) · 168/1,083,732 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.0125% 176/1,404,312 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0155%	6,451
Remaining individualsnot grpmax-eligible	0.00939%	10,649
South Asian	0.003%	33,300
African / African-American	0.00151%	66,364

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.Asp167Tyr
Coding: c.499G>T
MANE Select: NM_001365692
Type: single nucleotide variant
Location: chr20:32018975 (GRCh38)
Gene constraint: LOEUF 0.907 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.84
Residue 167: the 'disordered' region

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

Similar variants

CCM2L p.Asp167Gly Uncertain significance ★ ⚠ same residue
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

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-asp167tyr (accessed [today's date]).

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