Is BPHL p.Arg249Trp (c.745C>T) pathogenic?

BPHL p.Arg249Trp (c.745C>T) is classified Uncertain significance in BPHL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely benign (0.2242); Ultra-rare (popmax 0.0512%, eas).

How common is BPHL p.Arg249Trp (c.745C>T) in the general population?

BPHL p.Arg249Trp (c.745C>T) is ultra-rare (popmax 0.0512%, eas) (gnomAD).

What do computational predictors say about BPHL p.Arg249Trp (c.745C>T)?

AlphaMissense predicts likely benign (score 0.2242) — an in-silico prediction, not a clinical call.

BPHL p.Arg249Trp

c.745C>T · rs756888270 · VCV3134798

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2242 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0512%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2242	likely benign
REVEL	0.407	indeterminate
SaProt	LLR -13.52	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -1.7, phastCons 0.97
Regional constraint	o/e 0.95	unconstrained · MANE · 34 kb · p 0.31 · regional, not allelic
Overall
CADD	20.6	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 0.0512% East Asian · 23/44,896 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0296%

Overall 0.00409% 66/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0512%	1,952
Middle Eastern	0.0164%	6,084
European (non-Finnish)	0.00322%	31,053
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00134%	74,886
South Asian	0.0011%	91,080

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: BPHL
Protein: p.Arg249Trp
Coding: c.745C>T
MANE Select: NM_004332
dbSNP: rs756888270
Type: single nucleotide variant
Location: chr6:3140466 (GRCh38)
Gene constraint: LOEUF 1.262 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 92.43 · 4 PDB
Residue 249: an α-helix

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

Similar variants

BPHL p.Arg249Gln 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-arg249trp (accessed [today's date]).

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