Is BLTP3B p.Ser446Pro (c.1336T>C) pathogenic?

BLTP3B p.Ser446Pro (c.1336T>C) is classified Uncertain significance in BLTP3B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-13). AlphaMissense: likely benign (0.052); Ultra-rare (popmax 0.0178%, eas).

How common is BLTP3B p.Ser446Pro (c.1336T>C) in the general population?

BLTP3B p.Ser446Pro (c.1336T>C) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about BLTP3B p.Ser446Pro (c.1336T>C)?

AlphaMissense predicts likely benign (score 0.052) — an in-silico prediction, not a clinical call.

BLTP3B p.Ser446Pro

c.1336T>C · rs749735525 · VCV3134386

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.052 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.052	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -7.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.45	GERP -2.7, phastCons 0.8
Regional constraint	o/e 0.98	unconstrained · MANE · 51 kb · p 0.37 · regional, not allelic
Overall
CADD	11.64	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 0.0178% East Asian · 8/44,822 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000558% 9/1,613,764 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,603
Middle Eastern	0.0164%	6,080

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: BLTP3B
Protein: p.Ser446Pro
Coding: c.1336T>C
MANE Select: NM_015054
dbSNP: rs749735525
Type: single nucleotide variant
Location: chr12:100083087 (GRCh38)
Structure: AlphaFold pLDDT 67.53

Full BLTP3B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BLTP3B p.Leu491= Benign ★★ same type
BLTP3B p.Ala109Val Uncertain significance ★ ⚠ same type
BLTP3B p.Ala1162Thr Uncertain significance ★ ⚠ same type
BLTP3B p.Ala1272Ser Uncertain significance ★ ⚠ same type
BLTP3B p.Ala231Ser Uncertain significance ★ ⚠ same type
BLTP3B p.Ala231Thr Uncertain significance ★ ⚠ same type
BLTP3B p.Ala257Gly Uncertain significance ★ ⚠ same type
BLTP3B p.Ala66Thr Uncertain significance ★ ⚠ same type

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/bltp3b-p-ser446pro (accessed [today's date]).

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