Is BEST1 p.Phe375Val (c.1123T>G) pathogenic?

BEST1 p.Phe375Val (c.1123T>G) is classified Uncertain significance in BEST1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-14). AlphaMissense: likely pathogenic (0.6091); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BEST1 p.Phe375Val (c.1123T>G)?

BEST1 p.Phe375Val (c.1123T>G) is associated with Inborn genetic diseases (ClinVar).

How common is BEST1 p.Phe375Val (c.1123T>G) in the general population?

BEST1 p.Phe375Val (c.1123T>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about BEST1 p.Phe375Val (c.1123T>G)?

AlphaMissense predicts likely pathogenic (score 0.6091) — an in-silico prediction, not a clinical call.

BEST1 p.Phe375Val

c.1123T>G · rs756372609 · VCV1478822

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6091 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6091	likely pathogenic
REVEL	0.552	indeterminate
SaProt	LLR -5.34	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 0.39, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 12 kb · p 0.011 · regional, not allelic
Overall
CADD	20.2	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 0.000424% European (non-Finnish) · 5/1,179,918 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,824 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: BEST1
Protein: p.Phe375Val
Coding: c.1123T>G
MANE Select: NM_004183
dbSNP: rs756372609
Type: single nucleotide variant
Location: chr11:61962277 (GRCh38)
Gene constraint: LOEUF 1.28 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.46 · 19 PDB
Residue 375: the 'auto-inhibitory segment' region; a β-strand

Full BEST1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BEST1 p.Ala509Asp Uncertain significance ★★ ⚠ same condition
BEST1 p.Arg392Cys Uncertain significance ★★ ⚠ same condition
BEST1 p.Arg461Thr Uncertain significance ★★ ⚠ same condition
BEST1 p.Asn550Asp Uncertain significance ★★ ⚠ same condition
BEST1 p.Asp384Ala Uncertain significance ★★ ⚠ same condition
BEST1 p.Asp543Glu Uncertain significance ★★ ⚠ same condition
BEST1 p.Gln397Arg Uncertain significance ★★ ⚠ same condition
BEST1 p.Gln74Arg Uncertain significance ★★ ⚠ same condition

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/best1-p-phe375val (accessed [today's date]).

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