Is KRIT1 p.Val658= (c.1974G>A) pathogenic?

KRIT1 p.Val658= (c.1974G>A) is classified Uncertain significance in KRIT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-27). Very rare (popmax 8.48e-05%, nfe); Associated with angiokeratoma corporis diffusum with arteriovenous fistulas.

How common is KRIT1 p.Val658= (c.1974G>A) in the general population?

KRIT1 p.Val658= (c.1974G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

KRIT1 p.Val658=

Q: What condition is associated with KRIT1 p.Val658= (c.1974G>A)?

KRIT1 p.Val658= (c.1974G>A) is associated with angiokeratoma corporis diffusum with arteriovenous fistulas, cerebral cavernous malformation (ClinVar).

c.1974G>A · rs780889522 · VCV908345

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

angiokeratoma corporis diffusum with arteriovenous fistulas

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 -0.16	GERP 2, phastCons 0.26
Overall
CADD	7.002	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,598 alleles

Overall 6.2e-05% 1/1,613,550 alleles · very rare exomes 1/1,461,284 · genomes 0/152,266 · joint denominator

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.Val658=
Coding: c.1974G>A
MANE Select: NM_194454
dbSNP: rs780889522
Type: single nucleotide variant
Location: chr7:92213246 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 83.01 · 15 PDB
Residue 658: the ferm domain; a β-strand

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

Disease context

angiokeratoma corporis diffusum with arteriovenous fistulas — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cerebral cavernous malformation

Similar variants

KRIT1 p.Val658Met 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-val658 (accessed [today's date]).

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