Is BEND4 p.Ile334Met (c.1002T>G) pathogenic?

BEND4 p.Ile334Met (c.1002T>G) is classified Uncertain significance in BEND4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.2944); Very rare (popmax 0.00357%, sas).

How common is BEND4 p.Ile334Met (c.1002T>G) in the general population?

BEND4 p.Ile334Met (c.1002T>G) is very rare (popmax 0.00357%, sas) (gnomAD).

What do computational predictors say about BEND4 p.Ile334Met (c.1002T>G)?

AlphaMissense predicts likely benign (score 0.2944) — an in-silico prediction, not a clinical call.

BEND4 p.Ile334Met

c.1002T>G · VCV3991295

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00357%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2944	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -6.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.59, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 35 kb · p 0.85 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00357% South Asian · 3/84,064 alleles

Filtering AF 0.000948% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000463%

Overall 0.0005% 7/1,399,976 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00357%	28,021
European (non-Finnish)	0.000349%	286,784

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: BEND4
Protein: p.Ile334Met
Coding: c.1002T>G
MANE Select: NM_207406
Type: single nucleotide variant
Location: chr4:42143480 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.57

Full BEND4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BEND4 p.Gln224Glu Uncertain significance ★★ ⚠ same type
BEND4 p.Ser268Leu Uncertain significance ★★ ⚠ same type
BEND4 p.Pro473= Likely benign ★★ same type
BEND4 p.Ala125Thr Uncertain significance ★ ⚠ same type
BEND4 p.Ala244Pro Uncertain significance ★ ⚠ same type
BEND4 p.Ala518Pro Uncertain significance ★ ⚠ same type
BEND4 p.Ala66Val Uncertain significance ★ ⚠ same type
BEND4 p.Ala82Pro 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/bend4-p-ile334met (accessed [today's date]).

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