Is BEST3 p.Leu174Phe (c.520C>T) pathogenic?

BEST3 p.Leu174Phe (c.520C>T) is classified Uncertain significance in BEST3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-14). AlphaMissense: ambiguous (0.4295); Ultra-rare (popmax 0.0357%, eas).

How common is BEST3 p.Leu174Phe (c.520C>T) in the general population?

BEST3 p.Leu174Phe (c.520C>T) is ultra-rare (popmax 0.0357%, eas) (gnomAD).

What do computational predictors say about BEST3 p.Leu174Phe (c.520C>T)?

AlphaMissense predicts ambiguous (score 0.4295) — an in-silico prediction, not a clinical call.

BEST3 p.Leu174Phe

c.520C>T · VCV3824198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4295 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, eas)

Computational evidence

Protein change
AlphaMissense	0.4295	ambiguous
REVEL	0.634	indeterminate
SaProt	LLR -8.80	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 43 kb · p 0.069 · regional, not allelic
Overall
CADD	25.1	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 0.0357% East Asian · 16/44,858 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.000991% 16/1,613,938 alleles · ultra-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.Leu174Phe
Coding: c.520C>T
MANE Select: NM_032735
Type: single nucleotide variant
Location: chr12:69678855 (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-leu174phe (accessed [today's date]).

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