Is AFG2B p.Val245Glu (c.734T>A) pathogenic?

AFG2B p.Val245Glu (c.734T>A) is classified Likely pathogenic in AFG2B (ClinVar, Single submitter, 2 submitters; last evaluated 2021-09-13). AlphaMissense: likely pathogenic (0.7553); Very rare (popmax 0.00072%, nfe); Associated with neurodevelopmental disorder with hearing loss and spasticity.

What condition is associated with AFG2B p.Val245Glu (c.734T>A)?

AFG2B p.Val245Glu (c.734T>A) is associated with neurodevelopmental disorder with hearing loss and spasticity (ClinVar).

How common is AFG2B p.Val245Glu (c.734T>A) in the general population?

AFG2B p.Val245Glu (c.734T>A) is very rare (popmax 0.00072%, nfe) (gnomAD).

What do computational predictors say about AFG2B p.Val245Glu (c.734T>A)?

AlphaMissense predicts likely pathogenic (score 0.7553) — an in-silico prediction, not a clinical call.

AFG2B p.Val245Glu

c.734T>A · rs1230836596 · VCV1275861

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7553 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00072%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with hearing loss and spasticity

Computational evidence

Protein change
AlphaMissense	0.7553	likely pathogenic ✓ concordant with ClinVar
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -14.55	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 7.7	GERP 0.13, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 19 kb · p 0.58 · regional, not allelic
Overall
CADD	31.0	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 0.00072% European (non-Finnish) · 8/1,111,284 alleles

Filtering AF 0.00031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000224%

Overall 0.000552% 8/1,450,292 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.Val245Glu
Coding: c.734T>A
MANE Select: NM_024063
dbSNP: rs1230836596
Type: single nucleotide variant
Location: chr15:45403163 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 2 PDB
Residue 245: a UniProt-annotated variant site (in nedhls; no effect on interaction with afg2a and cinp; strongly reduces cell viability); a binding site

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.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
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-val245glu (accessed [today's date]).

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