Is BEGAIN p.Pro255Arg (c.764C>G) pathogenic?

BEGAIN p.Pro255Arg (c.764C>G) is classified Uncertain significance in BEGAIN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-08). AlphaMissense: ambiguous (0.4347); Very rare (popmax 0.000933%, nfe).

How common is BEGAIN p.Pro255Arg (c.764C>G) in the general population?

BEGAIN p.Pro255Arg (c.764C>G) is very rare (popmax 0.000933%, nfe) (gnomAD).

What do computational predictors say about BEGAIN p.Pro255Arg (c.764C>G)?

AlphaMissense predicts ambiguous (score 0.4347) — an in-silico prediction, not a clinical call.

BEGAIN p.Pro255Arg

c.764C>G · VCV3480403

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4347 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000933%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4347	ambiguous
REVEL	0.61	indeterminate
SaProt	LLR -6.55	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 1.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 1,319 bp · p 0.52 · 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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P236R vs ClinVar P255R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000933% European (non-Finnish) · 11/1,179,540 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000806% 13/1,612,232 alleles · very rare exomes 13/1,459,876 · genomes 0/152,356 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,197
European (non-Finnish)grpmax	0.000933%	107,231

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: BEGAIN
Protein: p.Pro255Arg
Coding: c.764C>G
MANE Select: NM_001385089
Type: single nucleotide variant
Location: chr14:100539044 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.19

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

Similar variants

BEGAIN p.Gly388Arg Uncertain significance ★★ ⚠ same type
BEGAIN p.Asp195Asn Benign ★★ same type
BEGAIN p.Pro237Gln Benign ★★ same type
BEGAIN p.Ala194Ser Uncertain significance ★ ⚠ same type
BEGAIN p.Ala221Gly Uncertain significance ★ ⚠ same type
BEGAIN p.Ala285Gly Uncertain significance ★ ⚠ same type
BEGAIN p.Ala339Thr Uncertain significance ★ ⚠ same type
BEGAIN p.Ala454Pro 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/begain-p-pro255arg (accessed [today's date]).

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