Is BPHL p.Pro96Ser (c.286C>T) pathogenic?

BPHL p.Pro96Ser (c.286C>T) is classified Uncertain significance in BPHL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.6548); Ultra-rare (popmax 0.0119%, eas).

How common is BPHL p.Pro96Ser (c.286C>T) in the general population?

BPHL p.Pro96Ser (c.286C>T) is ultra-rare (popmax 0.0119%, eas) (gnomAD).

What do computational predictors say about BPHL p.Pro96Ser (c.286C>T)?

AlphaMissense predicts likely pathogenic (score 0.6548) — an in-silico prediction, not a clinical call.

BPHL p.Pro96Ser

c.286C>T · VCV4646417

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6548 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0119%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6548	likely pathogenic
REVEL	0.458	indeterminate
SaProt	LLR -8.02	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 34 kb · p 0.31 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0119% East Asian · 5/42,046 alleles

Filtering AF 0.00468% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.000584% 9/1,542,070 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0119%	8,409
Admixed American	0.0073%	13,705

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: BPHL
Protein: p.Pro96Ser
Coding: c.286C>T
MANE Select: NM_004332
Type: single nucleotide variant
Location: chr6:3127316 (GRCh38)
Gene constraint: LOEUF 1.262 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 92.43 · 4 PDB
Residue 96: the ab hydrolase-1 domain

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

Similar variants

TUBB2A p.Thr178Met Pathogenic/Likely pathogenic ★★ same type
BPHL p.Ala164Pro Uncertain significance ★ ⚠ same type
BPHL p.Ala164Thr Uncertain significance ★ ⚠ same type
BPHL p.Ala166Thr Uncertain significance ★ ⚠ same type
BPHL p.Ala236Ser Uncertain significance ★ ⚠ same type
BPHL p.Ala252Val Uncertain significance ★ ⚠ same type
BPHL p.Ala34Ser Uncertain significance ★ ⚠ same type
BPHL p.Arg12Cys 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/bphl-p-pro96ser (accessed [today's date]).

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