Is BEST3 p.Leu137Pro (c.410T>C) pathogenic?

BEST3 p.Leu137Pro (c.410T>C) is classified Uncertain significance in BEST3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely pathogenic (0.9977); Very rare (popmax 8.47e-05%, nfe).

How common is BEST3 p.Leu137Pro (c.410T>C) in the general population?

BEST3 p.Leu137Pro (c.410T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about BEST3 p.Leu137Pro (c.410T>C)?

AlphaMissense predicts likely pathogenic (score 0.9977) — an in-silico prediction, not a clinical call.

BEST3 p.Leu137Pro

c.410T>C · VCV4645799

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9977	likely pathogenic · top 3% in BEST3
REVEL	0.963	strongly pathogenic-leaning
SaProt	LLR -11.36	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 43 kb · p 0.069 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,180,028 alleles

Overall 6.84e-05% 1/1,461,868 alleles · very rare

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: BEST3
Protein: p.Leu137Pro
Coding: c.410T>C
MANE Select: NM_032735
Type: single nucleotide variant
Location: chr12:69693745 (GRCh38)
Gene constraint: LOEUF 1.275 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.66

Full BEST3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BEST3 p.Pro383Leu Benign ★★ same type
BEST3 p.Val49= Benign ★★ same type
BEST3 p.Ala351Gly Uncertain significance ★ ⚠ same type
BEST3 p.Arg141Ser Uncertain significance ★ ⚠ same type
BEST3 p.Arg196Gln Uncertain significance ★ ⚠ same type
BEST3 p.Arg196Trp Uncertain significance ★ ⚠ same type
BEST3 p.Arg202Ile Uncertain significance ★ ⚠ same type
BEST3 p.Arg216Gly 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/best3-p-leu137pro (accessed [today's date]).

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