Is BEST4 p.Pro361Ser (c.1081C>T) pathogenic?

BEST4 p.Pro361Ser (c.1081C>T) is classified Uncertain significance in BEST4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely pathogenic (0.7191); Ultra-rare (popmax 0.066%, sas).

How common is BEST4 p.Pro361Ser (c.1081C>T) in the general population?

BEST4 p.Pro361Ser (c.1081C>T) is ultra-rare (popmax 0.066%, sas) (gnomAD).

What do computational predictors say about BEST4 p.Pro361Ser (c.1081C>T)?

AlphaMissense predicts likely pathogenic (score 0.7191) — an in-silico prediction, not a clinical call.

BEST4 p.Pro361Ser

c.1081C>T · VCV3991326

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7191 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7191	likely pathogenic
REVEL	0.746	pathogenic-leaning
SaProt	LLR -10.89	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 9.8	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 980 bp · p 0.062 · regional, not allelic
Overall
CADD	27.8	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 0.066% South Asian · 60/90,866 alleles

Filtering AF 0.0526% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0478%

Overall 0.00446% 72/1,612,566 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.066%	1,514
Remaining individualsnot grpmax-eligible	0.00801%	12,485
African / African-American	0.00133%	75,046
European (non-Finnish)	0.000509%	196,566

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: BEST4
Protein: p.Pro361Ser
Coding: c.1081C>T
MANE Select: NM_153274
Type: single nucleotide variant
Location: chr1:44784696 (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.Pro361Leu Uncertain significance ★ ⚠ same residue
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

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-pro361ser (accessed [today's date]).

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