Is BPI p.Tyr43His (c.127T>C) pathogenic?

BPI p.Tyr43His (c.127T>C) is classified Uncertain significance in BPI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: ambiguous (0.5062); Ultra-rare (popmax 0.011%, sas).

How common is BPI p.Tyr43His (c.127T>C) in the general population?

BPI p.Tyr43His (c.127T>C) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about BPI p.Tyr43His (c.127T>C)?

AlphaMissense predicts ambiguous (score 0.5062) — an in-silico prediction, not a clinical call.

BPI p.Tyr43His

c.127T>C · VCV4646421

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5062 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5062	ambiguous
REVEL	0.268	benign-leaning
SaProt	LLR -10.91	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 2.3, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 33 kb · p 0.094 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM Y47H vs ClinVar Y43H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.011% South Asian · 10/91,050 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.000753% 11/1,460,964 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,105
European (non-Finnish)	8.47e-05%	1,179,970

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: BPI
Protein: p.Tyr43His
Coding: c.127T>C
MANE Select: NM_001725
Type: single nucleotide variant
Location: chr20:38304350 (GRCh38)
Gene constraint: LOEUF 1.011 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.70 · 2 PDB
Residue 43: the 'n-terminal barrel' region; an α-helix

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

Similar variants

BPI p.Tyr43Cys Uncertain significance ★ ⚠ same residue
BPI c.664+7G>T Benign ★★ same type
BPI p.Ala12Val Benign ★★ same type
BPI p.Ala192Val Benign ★★ same type
BPI p.Ala333Thr Likely benign ★★ ⚠ same type
BPI p.Ala8Thr Benign ★★ same type
BPI p.Ala8Val Benign ★★ same type
BPI p.Arg86Cys Benign ★★ ⚠ 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/bpi-p-tyr43his (accessed [today's date]).

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