Is BPHL p.Lys151Glu (c.451A>G) pathogenic?

BPHL p.Lys151Glu (c.451A>G) is classified Uncertain significance in BPHL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-06). AlphaMissense: likely benign (0.1385); Ultra-rare (popmax 0.0165%, mid).

How common is BPHL p.Lys151Glu (c.451A>G) in the general population?

BPHL p.Lys151Glu (c.451A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about BPHL p.Lys151Glu (c.451A>G)?

AlphaMissense predicts likely benign (score 0.1385) — an in-silico prediction, not a clinical call.

BPHL p.Lys151Glu

c.451A>G · VCV3481594

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1385 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1385	likely benign
REVEL	0.413	indeterminate
SaProt	LLR -6.08	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.22	acceptor gain · deltas
Pangolin	Δ0.38	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.8	GERP 0.38, phastCons 0.044
Regional constraint	o/e 0.95	unconstrained · MANE · 34 kb · p 0.31 · regional, not allelic
Overall
CADD	22.6	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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000682% 11/1,613,692 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
Admixed American	0.00167%	59,934
Remaining individualsnot grpmax-eligible	0.0016%	62,478
African / African-American	0.00133%	74,932
European (non-Finnish)	0.000593%	168,551

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.Lys151Glu
Coding: c.451A>G
MANE Select: NM_004332
Type: single nucleotide variant
Location: chr6:3129117 (GRCh38)
Gene constraint: LOEUF 1.262 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 92.43 · 4 PDB
Residue 151: the ab hydrolase-1 domain; an α-helix

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

Similar variants

BPHL p.Lys151Arg Uncertain significance ★ ⚠ same residue
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

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-lys151glu (accessed [today's date]).

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