Is BPHL p.Ala127Val (c.380C>T) pathogenic?

BPHL p.Ala127Val (c.380C>T) is classified Benign in BPHL (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-19). AlphaMissense: likely benign (0.0968); Low-frequency (popmax 2.76%, sas).

How common is BPHL p.Ala127Val (c.380C>T) in the general population?

BPHL p.Ala127Val (c.380C>T) is low-frequency (popmax 2.76%, sas) (gnomAD).

What do computational predictors say about BPHL p.Ala127Val (c.380C>T)?

AlphaMissense predicts likely benign (score 0.0968) — an in-silico prediction, not a clinical call.

BPHL p.Ala127Val

c.380C>T · rs2231366 · VCV709823

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0968 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.76%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0968	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -9.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.37	acceptor loss, 46 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.9	GERP 1.4
Regional constraint	o/e 0.95	unconstrained · MANE · 34 kb · p 0.31 · regional, not allelic
Overall
CADD	14.37	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 2.76% South Asian · 2,513/91,076 alleles

Filtering AF 2.67% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.63%

Overall 0.308% 4,965/1,614,190 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	2.76%	36
African / African-American	2.29%	44
East Asian	0.864%	116
Remaining individualsnot grpmax-eligible	0.358%	279
Middle Eastern	0.198%	505
Admixed American	0.12%	834
European (non-Finnish)	0.00331%	30,257

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.Ala127Val
Coding: c.380C>T
MANE Select: NM_004332
dbSNP: rs2231366
Type: single nucleotide variant
Location: chr6:3129046 (GRCh38)
Gene constraint: LOEUF 1.262 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 92.43 · 4 PDB
Residue 127: the ab hydrolase-1 domain; an α-helix

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-ala127val (accessed [today's date]).

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