Is KRIT1 p.Arg185Pro (c.554G>C) pathogenic?

KRIT1 p.Arg185Pro (c.554G>C) is classified Uncertain significance in KRIT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-13). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1; Associated with cerebral cavernous malformation.

What condition is associated with KRIT1 p.Arg185Pro (c.554G>C)?

KRIT1 p.Arg185Pro (c.554G>C) is associated with cerebral cavernous malformation (ClinVar).

How common is KRIT1 p.Arg185Pro (c.554G>C) in the general population?

KRIT1 p.Arg185Pro (c.554G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KRIT1 p.Arg185Pro (c.554G>C)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

KRIT1 p.Arg185Pro

c.554G>C · VCV3640405

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebral cavernous malformation

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic · top 1% in KRIT1
REVEL	0.864	moderately pathogenic-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 3.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 6,702 bp · p 0.49 · regional, not allelic
Overall
CADD	26.6	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: KRIT1
Protein: p.Arg185Pro
Coding: c.554G>C
MANE Select: NM_194454
Type: single nucleotide variant
Location: chr7:92235578 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 83.01 · 15 PDB
Residue 185: an α-helix; the 'interaction with itgb1bp1' region

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.Arg185Trp 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-arg185pro (accessed [today's date]).

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