Is AFG2B p.Arg64Trp (c.190C>T) pathogenic?

AFG2B p.Arg64Trp (c.190C>T) is classified Likely pathogenic in AFG2B (ClinVar, Single submitter, 2 submitters; last evaluated 2021-08-27). AlphaMissense: likely pathogenic (0.5787); Very rare (popmax 0.000343%, nfe); Associated with neurodevelopmental disorder with hearing loss and spasticity.

What condition is associated with AFG2B p.Arg64Trp (c.190C>T)?

AFG2B p.Arg64Trp (c.190C>T) is associated with neurodevelopmental disorder with hearing loss and spasticity (ClinVar).

How common is AFG2B p.Arg64Trp (c.190C>T) in the general population?

AFG2B p.Arg64Trp (c.190C>T) is very rare (popmax 0.000343%, nfe) (gnomAD).

What do computational predictors say about AFG2B p.Arg64Trp (c.190C>T)?

AlphaMissense predicts likely pathogenic (score 0.5787) — an in-silico prediction, not a clinical call.

AFG2B p.Arg64Trp

c.190C>T · rs1212383243 · VCV1275865

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5787 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000343%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neurodevelopmental disorder with hearing loss and spasticity

Computational evidence

Protein change
AlphaMissense	0.5787	likely pathogenic ✓ concordant with ClinVar
REVEL	0.622	indeterminate
SaProt	LLR -13.25	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 4.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 19 kb · p 0.58 · regional, not allelic
Overall
CADD	26.4	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 0.000343% European (non-Finnish) · 4/1,165,272 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000254% 4/1,576,742 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: AFG2B
Protein: p.Arg64Trp
Coding: c.190C>T
MANE Select: NM_024063
dbSNP: rs1212383243
Type: single nucleotide variant
Location: chr15:45402619 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 2 PDB
Residue 64: the 'required for interaction with afg2a and cinp' region; a UniProt-annotated variant site (in nedhls; strongly reduces interaction with afg2a and cinp; reduces cell viability)

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.Arg64Gln Uncertain significance ★ same residue
AFG2B p.Ile466Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
AFG2B p.Thr400Ile Pathogenic/Likely pathogenic ★★ same condition
AFG2B p.Arg288Pro Uncertain significance ★★ ⚠ same condition
AFG2B p.Phe71Leu Uncertain significance ★★ ⚠ same condition
AFG2B p.Leu270Pro Likely pathogenic ★ same condition
AFG2B p.Leu438Pro Likely pathogenic ★ same condition
AFG2B p.Met669Arg Likely 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-arg64trp (accessed [today's date]).

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