Is BPI p.Ala12Val (c.35C>T) pathogenic?

BPI p.Ala12Val (c.35C>T) is classified Benign in BPI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2016-03-28). AlphaMissense: likely benign (0.1181); Common (popmax 60.2%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about BPI p.Ala12Val (c.35C>T)?

AlphaMissense predicts likely benign (score 0.1181) — an in-silico prediction, not a clinical call.

BPI p.Ala12Val

Q: How common is BPI p.Ala12Val (c.35C>T) in the general population?

BPI p.Ala12Val (c.35C>T) is common (popmax 60.2%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.35C>T · rs1341023 · VCV402430

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1181 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 60.2%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1181	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -5.97	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 2	GERP 1.1, phastCons 0.96
Regional constraint	o/e 1.07	unconstrained · MANE · 33 kb · p 0.094 · regional, not allelic
Overall
CADD	17.41	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 A16V vs ClinVar A12V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 60.2% East Asian · 26,997/44,846 alleles

Filtering AF 59.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 59.4%

Overall 52.2% 843,083/1,613,624 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	65%	2
East Asiangrpmax	60.2%	2
Amishnot grpmax-eligible	58.3%	2
Middle Eastern	56.6%	2
Admixed American	54.2%	2
European (non-Finnish)	54.2%	2
Remaining individualsnot grpmax-eligible	52%	2
South Asian	49.7%	2
Finnishnot grpmax-eligible	44.3%	2
African / African-American	20.6%	5

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala12Val
Coding: c.35C>T
MANE Select: NM_001725
dbSNP: rs1341023
Type: single nucleotide variant
Location: chr20:38304258 (GRCh38)
Gene constraint: LOEUF 1.011 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.70 · 2 PDB
Residue 12: a UniProt-annotated variant site (in)

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

Similar variants

BPI c.664+7G>T 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
BPI p.Glu136Gln Benign ★★ same type
BPI p.Glu212Lys 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-ala12val (accessed [today's date]).

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