Is BLTP1 p.Val770Ile (c.2308G>A) pathogenic?

BLTP1 p.Val770Ile (c.2308G>A) is classified Conflicting classifications of pathogenicity in BLTP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-26). AlphaMissense: likely benign (0.1008); Rare (popmax 0.206%, sas); Associated with Alkuraya-Kucinskas syndrome.

What condition is associated with BLTP1 p.Val770Ile (c.2308G>A)?

BLTP1 p.Val770Ile (c.2308G>A) is associated with Alkuraya-Kucinskas syndrome (ClinVar).

How common is BLTP1 p.Val770Ile (c.2308G>A) in the general population?

BLTP1 p.Val770Ile (c.2308G>A) is rare (popmax 0.206%, sas) (gnomAD).

What do computational predictors say about BLTP1 p.Val770Ile (c.2308G>A)?

AlphaMissense predicts likely benign (score 0.1008) — an in-silico prediction, not a clinical call.

BLTP1 p.Val770Ile

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.2308G>A · rs373369660 · VCV2433106

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1008 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.206%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Alkuraya-Kucinskas syndrome

Computational evidence

Protein change
AlphaMissense	0.1008	likely benign
REVEL	0.258	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 45 kb · p 1e-08 · regional, not allelic
Overall
CADD	22.3	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 0.206% South Asian · 188/91,086 alleles

Filtering AF 0.182% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.173%

Overall 0.0232% 375/1,614,136 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.206%	485
Middle Eastern	0.115%	866
Remaining individualsnot grpmax-eligible	0.0144%	6,945
Admixed American	0.0133%	7,502
European (non-Finnish)	0.0132%	7,564
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,801
Finnishnot grpmax-eligible	0.00469%	21,343
African / African-American	0.00267%	37,521

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.Val770Ile
Coding: c.2308G>A
MANE Select: NM_001384125
dbSNP: rs373369660
Type: single nucleotide variant
Location: chr4:122219400 (GRCh38)
Residue 770: a UniProt-annotated variant site (in alkkucs)

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-val770ile (accessed [today's date]).

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