Is BEND4 p.Ile419Phe (c.1255A>T) pathogenic?

BEND4 p.Ile419Phe (c.1255A>T) is classified Uncertain significance in BEND4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-27). AlphaMissense: likely pathogenic (0.9971); Very rare (popmax 6.84e-05%).

How common is BEND4 p.Ile419Phe (c.1255A>T) in the general population?

BEND4 p.Ile419Phe (c.1255A>T) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about BEND4 p.Ile419Phe (c.1255A>T)?

AlphaMissense predicts likely pathogenic (score 0.9971) — an in-silico prediction, not a clinical call.

BEND4 p.Ile419Phe

c.1255A>T · rs1260231611 · VCV3133693

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9971 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9971	likely pathogenic · top 8% in BEND4
REVEL	0.602	indeterminate
SaProt	LLR -10.50	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 35 kb · p 0.85 · regional, not allelic
Overall
CADD	29.9	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 6.84e-05%

Overall 6.84e-05% 1/1,461,712 alleles · very rare

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.Ile419Phe
Coding: c.1255A>T
MANE Select: NM_207406
dbSNP: rs1260231611
Type: single nucleotide variant
Location: chr4:42120186 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.57
Residue 419: the ben domain

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-ile419phe (accessed [today's date]).

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