Is BEST4 p.Val143Ala (c.428T>C) pathogenic?

BEST4 p.Val143Ala (c.428T>C) is classified Uncertain significance in BEST4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). AlphaMissense: likely pathogenic (0.9428); Absent from gnomAD v4.1.

How common is BEST4 p.Val143Ala (c.428T>C) in the general population?

BEST4 p.Val143Ala (c.428T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BEST4 p.Val143Ala (c.428T>C)?

AlphaMissense predicts likely pathogenic (score 0.9428) — an in-silico prediction, not a clinical call.

BEST4 p.Val143Ala

c.428T>C · VCV3480494

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9428 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,548,220)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9428	likely pathogenic
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -11.33	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.20	donor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 2,460 bp · p 0.0055 · regional, not allelic
Overall
CADD	28.2	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

No allele count reported in gnomAD v4.1 (AN 1,548,220). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: BEST4
Protein: p.Val143Ala
Coding: c.428T>C
MANE Select: NM_153274
Type: single nucleotide variant
Location: chr1:44786516 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.51

Full BEST4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BEST4 p.Thr55= Benign ★★ same type
BEST4 p.Ala112Val Uncertain significance ★ ⚠ same type
BEST4 p.Ala195Gly Uncertain significance ★ ⚠ same type
BEST4 p.Ala249Ser Uncertain significance ★ ⚠ same type
BEST4 p.Ala265Thr Uncertain significance ★ ⚠ same type
BEST4 p.Ala368Asp Uncertain significance ★ ⚠ same type
BEST4 p.Ala44Thr Uncertain significance ★ ⚠ same type
BEST4 p.Ala464Val 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/best4-p-val143ala (accessed [today's date]).

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