Is BLTP1 p.Pro2369Thr (c.7105C>A) pathogenic?

BLTP1 p.Pro2369Thr (c.7105C>A) is classified Uncertain significance in BLTP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-03). AlphaMissense: likely benign (0.0804); Ultra-rare (popmax 0.0518%, sas); Associated with Alkuraya-Kucinskas syndrome.

What condition is associated with BLTP1 p.Pro2369Thr (c.7105C>A)?

BLTP1 p.Pro2369Thr (c.7105C>A) is associated with Alkuraya-Kucinskas syndrome (ClinVar).

How common is BLTP1 p.Pro2369Thr (c.7105C>A) in the general population?

BLTP1 p.Pro2369Thr (c.7105C>A) is ultra-rare (popmax 0.0518%, sas) (gnomAD).

What do computational predictors say about BLTP1 p.Pro2369Thr (c.7105C>A)?

AlphaMissense predicts likely benign (score 0.0804) — an in-silico prediction, not a clinical call.

BLTP1 p.Pro2369Thr

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.7105C>A · rs534326417 · VCV1676331

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0804 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0518%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Alkuraya-Kucinskas syndrome

Computational evidence

Protein change
AlphaMissense	0.0804	likely benign
REVEL	0.246	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 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 21 kb · p 3.1e-07 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0518% South Asian · 47/90,724 alleles

Filtering AF 0.04% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0358%

Overall 0.00323% 52/1,611,904 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0518%	1,930
Remaining individualsnot grpmax-eligible	0.0032%	31,208
Admixed American	0.00168%	59,638
European (non-Finnish)	0.00017%	589,470

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.Pro2369Thr
Coding: c.7105C>A
MANE Select: NM_001384125
dbSNP: rs534326417
Type: single nucleotide variant
Location: chr4:122263564 (GRCh38)
Residue 2369: 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-pro2369thr (accessed [today's date]).

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