Is BEST1 p.Pro274Arg (c.821C>G) pathogenic?

BEST1 p.Pro274Arg (c.821C>G) is classified Pathogenic/Likely pathogenic in BEST1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-23). AlphaMissense: likely pathogenic (0.9959); Ultra-rare (popmax 0.0167%, amr); Associated with BEST1-related disorder.

What condition is associated with BEST1 p.Pro274Arg (c.821C>G)?

BEST1 p.Pro274Arg (c.821C>G) is associated with BEST1-related disorder, retinal disorder (ClinVar).

How common is BEST1 p.Pro274Arg (c.821C>G) in the general population?

BEST1 p.Pro274Arg (c.821C>G) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about BEST1 p.Pro274Arg (c.821C>G)?

AlphaMissense predicts likely pathogenic (score 0.9959) — an in-silico prediction, not a clinical call.

BEST1 p.Pro274Arg

c.821C>G · rs62639270 · VCV851138

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9959 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BEST1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9959	likely pathogenic ✓ concordant with ClinVar · top 2% in BEST1
REVEL	0.954	strongly pathogenic-leaning
SaProt	LLR -12.71	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 5.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 12 kb · p 0.011 · regional, not allelic
Overall
CADD	25.9	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 0.0167% Admixed American · 10/60,004 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00112% 18/1,614,102 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,000
African / African-American	0.00667%	14,988
Remaining individualsnot grpmax-eligible	0.0048%	20,827

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.Pro274Arg
Coding: c.821C>G
MANE Select: NM_004183
dbSNP: rs62639270
Type: single nucleotide variant
Location: chr11:61958252 (GRCh38)
Gene constraint: LOEUF 1.28 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.46 · 19 PDB

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

Disease context

Also linked: retinal disorder

Similar variants

BEST1 p.Pro274His Likely pathogenic ★ same residue
BEST1 p.Pro274= Conflicting classifications of pathogenicity ★ same residue
BEST1 c.636+1G>A Pathogenic ★★ same condition
BEST1 p.Ala10Val Pathogenic ★★ same condition
BEST1 p.Ala243Val Pathogenic/Likely pathogenic ★★ same condition
BEST1 p.Arg105Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
BEST1 p.Arg130Ser Pathogenic/Likely pathogenic ★★ same condition
BEST1 p.Arg13Cys Pathogenic/Likely pathogenic ★★ ⚠ 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-pro274arg (accessed [today's date]).

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