Is BECN2 p.Arg243Met (c.728G>T) pathogenic?

BECN2 p.Arg243Met (c.728G>T) is classified Benign in BECN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.1061); Common (popmax 38.9%, mid) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about BECN2 p.Arg243Met (c.728G>T)?

AlphaMissense predicts likely benign (score 0.1061) — an in-silico prediction, not a clinical call.

BECN2 p.Arg243Met

Q: How common is BECN2 p.Arg243Met (c.728G>T) in the general population?

BECN2 p.Arg243Met (c.728G>T) is common (popmax 38.9%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.728G>T · rs3851304 · VCV767772

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1061 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 38.9%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.1061	likely benign
SaProt	LLR -5.73	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.71	GERP -0.41
Regional constraint	o/e 0.84	unconstrained · MANE · 1,292 bp · p 0.00039 · regional, not allelic
Overall
CADD	8.795	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 38.9% Middle Eastern · 1,248/3,210 alleles

Filtering AF 37.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 36.4%

Overall 35.3% 435,162/1,231,476 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	46.4%	2
Middle Easterngrpmax	38.9%	3
Ashkenazi Jewishnot grpmax-eligible	38.7%	3
Finnishnot grpmax-eligible	37.8%	3
European (non-Finnish)	36.4%	3
Remaining individualsnot grpmax-eligible	35.3%	3
Admixed American	29.3%	3
African / African-American	27.8%	4
South Asian	26.1%	4
East Asian	24.7%	4

Amish 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: BECN2
Protein: p.Arg243Met
Coding: c.728G>T
MANE Select: NM_001290693
dbSNP: rs3851304
Type: single nucleotide variant
Location: chr1:241958494 (GRCh38)
Gene constraint: LOEUF 1.528 · pLI 0.48 (gnomAD)
Structure: AlphaFold pLDDT 77.12 · 4 PDB
Residue 243: an α-helix; the 'required for homodimer formation' region

Full BECN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BECN2 p.Glu158Lys Benign ★★ same type
BECN2 p.Ile103Met Benign ★★ same type
BECN2 p.Cys121Ter Uncertain significance ★ same type
BECN2 p.Leu272= Likely benign ★ 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/becn2-p-arg243met (accessed [today's date]).

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