Is AFG2B p.Ala83Val (c.248C>T) pathogenic?

AFG2B p.Ala83Val (c.248C>T) is classified Uncertain significance in AFG2B (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-17). AlphaMissense: likely benign (0.0929); Rare (popmax 0.175%, eas); Associated with neurodevelopmental disorder with hearing loss and spasticity.

What condition is associated with AFG2B p.Ala83Val (c.248C>T)?

AFG2B p.Ala83Val (c.248C>T) is associated with neurodevelopmental disorder with hearing loss and spasticity (ClinVar).

How common is AFG2B p.Ala83Val (c.248C>T) in the general population?

AFG2B p.Ala83Val (c.248C>T) is rare (popmax 0.175%, eas) (gnomAD).

What do computational predictors say about AFG2B p.Ala83Val (c.248C>T)?

AlphaMissense predicts likely benign (score 0.0929) — an in-silico prediction, not a clinical call.

AFG2B p.Ala83Val

c.248C>T · VCV4852933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0929 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.175%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with hearing loss and spasticity

Computational evidence

Protein change
AlphaMissense	0.0929	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -8.14	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 1.4	GERP -0.45, phastCons 0.001
Regional constraint	o/e 0.98	unconstrained · MANE · 19 kb · p 0.58 · regional, not allelic
Overall
CADD	10.77	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 0.175% East Asian · 75/42,952 alleles

Filtering AF 0.143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.131%

Overall 0.00666% 105/1,576,334 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.175%	573
South Asian	0.0172%	5,815
Remaining individualsnot grpmax-eligible	0.00981%	10,195
Admixed American	0.00352%	28,387
Finnishnot grpmax-eligible	0.00192%	51,968
European (non-Finnish)	0.000514%	194,506

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.Ala83Val
Coding: c.248C>T
MANE Select: NM_024063
Type: single nucleotide variant
Location: chr15:45402677 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 2 PDB
Residue 83: the 'required for interaction with afg2a and cinp' region

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.Ala83Thr 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.Arg64Trp Likely pathogenic ★ same condition
AFG2B p.Leu270Pro Likely pathogenic ★ same condition
AFG2B p.Leu438Pro 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-ala83val (accessed [today's date]).

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