Is BLTP1 p.Val653Phe (c.1957G>T) pathogenic?

BLTP1 p.Val653Phe (c.1957G>T) is classified Uncertain significance in BLTP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-01). AlphaMissense: likely pathogenic (0.7942); Ultra-rare (popmax 0.033%, mid); Associated with Alkuraya-Kucinskas syndrome.

What condition is associated with BLTP1 p.Val653Phe (c.1957G>T)?

BLTP1 p.Val653Phe (c.1957G>T) is associated with Alkuraya-Kucinskas syndrome (ClinVar).

How common is BLTP1 p.Val653Phe (c.1957G>T) in the general population?

BLTP1 p.Val653Phe (c.1957G>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about BLTP1 p.Val653Phe (c.1957G>T)?

AlphaMissense predicts likely pathogenic (score 0.7942) — an in-silico prediction, not a clinical call.

BLTP1 p.Val653Phe

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.1957G>T · rs201634837 · VCV2579733

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7942 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

Alkuraya-Kucinskas syndrome

Computational evidence

Protein change
AlphaMissense	0.7942	likely pathogenic
REVEL	0.436	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 45 kb · p 1e-08 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,054 alleles

Filtering AF 0.0173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0165%

Overall 0.0152% 246/1,613,516 alleles · ultra-rare exomes 225/1,461,276 · genomes 21/152,240 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,027
European (non-Finnish)	0.0194%	5,151
Admixed American	0.0183%	5,452
Remaining individualsnot grpmax-eligible	0.0048%	20,821
South Asian	0.0011%	91,078

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.Val653Phe
Coding: c.1957G>T
MANE Select: NM_001384125
dbSNP: rs201634837
Type: single nucleotide variant
Location: chr4:122209843 (GRCh38)
Residue 653: 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-val653phe (accessed [today's date]).

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