Is KRIT1 p.Ser25Phe (c.74C>T) pathogenic?

KRIT1 p.Ser25Phe (c.74C>T) is classified Uncertain significance in KRIT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-21). AlphaMissense: ambiguous (0.5526); Ultra-rare (popmax 0.0112%, eas); Associated with Inborn genetic diseases.

What condition is associated with KRIT1 p.Ser25Phe (c.74C>T)?

KRIT1 p.Ser25Phe (c.74C>T) is associated with Inborn genetic diseases, cerebral cavernous malformation (ClinVar).

How common is KRIT1 p.Ser25Phe (c.74C>T) in the general population?

KRIT1 p.Ser25Phe (c.74C>T) is ultra-rare (popmax 0.0112%, eas) (gnomAD).

What do computational predictors say about KRIT1 p.Ser25Phe (c.74C>T)?

AlphaMissense predicts ambiguous (score 0.5526) — an in-silico prediction, not a clinical call.

KRIT1 p.Ser25Phe

c.74C>T · rs779446044 · VCV1759205

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5526 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5526	ambiguous
REVEL	0.527	indeterminate
SaProt	LLR -5.54	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 3.8, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 6,702 bp · p 0.49 · regional, not allelic
Overall
CADD	28.2	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 0.0112% East Asian · 5/44,644 alleles

Filtering AF 0.00436% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00277%

Overall 0.000758% 12/1,582,678 alleles · ultra-rare exomes 11/1,430,710 · genomes 1/151,968 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0112%	8,929
Remaining individualsnot grpmax-eligible	0.00976%	10,245
European (non-Finnish)	8.68e-05%	1,151,991

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.Ser25Phe
Coding: c.74C>T
MANE Select: NM_194454
dbSNP: rs779446044
Type: single nucleotide variant
Location: chr7:92242062 (GRCh38)
Gene constraint: LOEUF 0.69 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 83.01 · 15 PDB
Residue 25: the 'n-terminal domain similar to nudix hydrolase domain' region

Full KRIT1 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

Also linked: cerebral cavernous malformation

Similar variants

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
KRIT1 c.1563+1G>A 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-ser25phe (accessed [today's date]).

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