Is CCM2 p.Arg307His (c.920G>A) pathogenic?

CCM2 p.Arg307His (c.920G>A) is classified Conflicting classifications of pathogenicity in CCM2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-05-06). AlphaMissense: likely pathogenic (0.5735); Very rare (popmax 0.00667%, afr); Associated with Inborn genetic diseases.

What condition is associated with CCM2 p.Arg307His (c.920G>A)?

CCM2 p.Arg307His (c.920G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CCM2 p.Arg307His (c.920G>A) in the general population?

CCM2 p.Arg307His (c.920G>A) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about CCM2 p.Arg307His (c.920G>A)?

AlphaMissense predicts likely pathogenic (score 0.5735) — an in-silico prediction, not a clinical call.

CCM2 p.Arg307His

c.920G>A · rs372739455 · VCV2521263

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5735 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5735	likely pathogenic
REVEL	0.294	indeterminate
SaProt	LLR -7.54	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.5	GERP 0.81, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 76 kb · p 3.5e-05 · 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 0.00667% African / African-American · 5/74,936 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00248% 40/1,613,424 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,290
African / African-Americangrpmax	0.00667%	14,987
South Asian	0.00439%	22,773
European (non-Finnish)	0.00169%	59,002
Admixed American	0.00167%	59,994
Remaining individualsnot grpmax-eligible	0.0016%	62,484

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CCM2
Protein: p.Arg307His
Coding: c.920G>A
MANE Select: NM_031443
dbSNP: rs372739455
Type: single nucleotide variant
Location: chr7:45074274 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.48 · 8 PDB
Residue 307: the 'harmonin homology domain' region; a turn

Full CCM2 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

CCM2 p.Ala186Thr Uncertain significance ★★ ⚠ same condition
CCM2 p.Arg326His Uncertain significance ★★ ⚠ same condition
CCM2 p.Arg423Pro Uncertain significance ★★ ⚠ same condition
CCM2 p.Gln441Arg Uncertain significance ★★ ⚠ same condition
CCM2 p.Ile131Asn Uncertain significance ★★ ⚠ same condition
CCM2 p.Pro102Leu Uncertain significance ★★ ⚠ same condition
CCM2 p.Val374Met Uncertain significance ★★ ⚠ same condition
CCM2 p.Arg378= Likely benign ★★ 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/ccm2-p-arg307his (accessed [today's date]).

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