Is AFG2B p.Arg288Pro (c.863G>C) pathogenic?

AFG2B p.Arg288Pro (c.863G>C) is classified Uncertain significance in AFG2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.6353); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with hearing loss and spasticity.

What condition is associated with AFG2B p.Arg288Pro (c.863G>C)?

AFG2B p.Arg288Pro (c.863G>C) is associated with neurodevelopmental disorder with hearing loss and spasticity (ClinVar).

How common is AFG2B p.Arg288Pro (c.863G>C) in the general population?

AFG2B p.Arg288Pro (c.863G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AFG2B p.Arg288Pro (c.863G>C)?

AlphaMissense predicts likely pathogenic (score 0.6353) — an in-silico prediction, not a clinical call.

AFG2B p.Arg288Pro

c.863G>C · rs2542045064 · VCV2581993

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6353 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with hearing loss and spasticity

Computational evidence

Protein change
AlphaMissense	0.6353	likely pathogenic
REVEL	0.652	pathogenic-leaning
SaProt	LLR -16.41	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 7.4	GERP 1.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 19 kb · p 0.58 · 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AFG2B
Protein: p.Arg288Pro
Coding: c.863G>C
MANE Select: NM_024063
dbSNP: rs2542045064
Type: single nucleotide variant
Location: chr15:45403292 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 2 PDB

Full AFG2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with hearing loss and spasticity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AFG2B p.Ile466Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
AFG2B p.Thr400Ile Pathogenic/Likely pathogenic ★★ same condition
AFG2B p.Phe71Leu Uncertain significance ★★ ⚠ same condition
AFG2B p.Arg64Trp Likely pathogenic ★ same condition
AFG2B p.Leu270Pro Likely pathogenic ★ same condition
AFG2B p.Leu438Pro Likely pathogenic ★ ⚠ same condition
AFG2B p.Met669Arg Likely pathogenic ★ ⚠ same condition
AFG2B p.Ser609Ter Pathogenic ★ same condition

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/afg2b-p-arg288pro (accessed [today's date]).

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