Is BLTP1 p.Arg258Ter (c.772C>T) pathogenic?

BLTP1 p.Arg258Ter (c.772C>T) is classified Likely pathogenic in BLTP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-18). Very rare (popmax 0.0018%, amr); Associated with Alkuraya-Kucinskas syndrome.

What condition is associated with BLTP1 p.Arg258Ter (c.772C>T)?

BLTP1 p.Arg258Ter (c.772C>T) is associated with Alkuraya-Kucinskas syndrome (ClinVar).

How common is BLTP1 p.Arg258Ter (c.772C>T) in the general population?

BLTP1 p.Arg258Ter (c.772C>T) is very rare (popmax 0.0018%, amr) (gnomAD).

BLTP1 p.Arg258Ter

Q: How is KIAA1109-related early lethal congenital brain malformations-arthrogryposis syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.772C>T · rs1200235313 · VCV2440988

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0018%, amr)

Conditions

Alkuraya-Kucinskas syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 88
REVEL	0.332	indeterminate
Splicing
SpliceAI	Δ0.40	donor loss · deltas
Pangolin	Δ0.42	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4	GERP 2.4, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0018% Admixed American · 1/55,478 alleles

Filtering AF 0.000549% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000433%

Overall 0.000886% 14/1,580,398 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0018%	55,478
South Asian	0.0012%	83,376
European (non-Finnish)	0.00103%	97,203

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: BLTP1
Protein: p.Arg258Ter
Coding: c.772C>T
MANE Select: NM_001384125
dbSNP: rs1200235313
Type: single nucleotide variant
Location: chr4:122188039 (GRCh38)

Full BLTP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Alkuraya-Kucinskas syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For KIAA1109-related early lethal congenital brain malformations-arthrogryposis syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal

Similar variants

BLTP1 p.Arg968Cys Likely pathogenic ★★ ⚠ same condition
BLTP1 p.Arg3665Gln Uncertain significance ★★ ⚠ same condition
BLTP1 p.Arg3884Trp Uncertain significance ★★ same condition
BLTP1 p.Arg50Trp Uncertain significance ★★ same condition
BLTP1 p.Asp3074Glu Uncertain significance ★★ ⚠ same condition
BLTP1 p.Asp998Tyr Uncertain significance ★★ ⚠ same condition
BLTP1 p.Gln1511His Uncertain significance ★★ ⚠ same condition
BLTP1 p.Gly1016Ser Uncertain significance ★★ ⚠ 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/bltp1-p-arg258ter (accessed [today's date]).

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