Is KRIT1 p.Pro378= (c.1134A>T) pathogenic?

KRIT1 p.Pro378= (c.1134A>T) is classified Likely benign in KRIT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-07-29). Ultra-rare (popmax 0.0496%, mid); Associated with cerebral cavernous malformation.

What condition is associated with KRIT1 p.Pro378= (c.1134A>T)?

KRIT1 p.Pro378= (c.1134A>T) is associated with cerebral cavernous malformation (ClinVar).

How common is KRIT1 p.Pro378= (c.1134A>T) in the general population?

KRIT1 p.Pro378= (c.1134A>T) is ultra-rare (popmax 0.0496%, mid) (gnomAD).

KRIT1 p.Pro378=

c.1134A>T · rs752464613 · VCV468204

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, mid)

Conditions

cerebral cavernous malformation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP 2.5, phastCons 1
Overall
CADD	8.603	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0496% Middle Eastern · 3/6,054 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00719%

Overall 0.000931% 15/1,611,914 alleles · ultra-rare exomes 15/1,459,598 · genomes 0/152,316 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0496%	2,018
South Asian	0.00439%	22,760
Remaining individualsnot grpmax-eligible	0.0032%	31,220
Admixed American	0.00167%	60,018
European (non-Finnish)	0.000424%	235,613

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: KRIT1
Protein: p.Pro378=
Coding: c.1134A>T
MANE Select: NM_194454
dbSNP: rs752464613
Type: single nucleotide variant
Location: chr7:92226538 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 83.01 · 15 PDB

Full KRIT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cerebral cavernous malformation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KRIT1 p.Pro378Leu Uncertain significance ★ ⚠ same residue
KRIT1 c.1146+1G>A Pathogenic ★★ same condition
KRIT1 c.1146+1G>T Pathogenic ★★ same condition
KRIT1 c.1147-13C>G Pathogenic ★★ same condition
KRIT1 c.1147-2A>G Pathogenic/Likely pathogenic ★★ same condition
KRIT1 c.1255-1G>A Pathogenic ★★ same condition
KRIT1 c.1255-2A>G Pathogenic ★★ same condition
KRIT1 c.1412-2A>C Pathogenic ★★ 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/krit1-p-pro378 (accessed [today's date]).

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