Is AFG2B p.Ser609Ter (c.1826C>G) pathogenic?

AFG2B p.Ser609Ter (c.1826C>G) is classified Pathogenic in AFG2B (ClinVar, Single submitter, 2 submitters; last evaluated 2021-07-29). Very rare (popmax 0.00134%, afr); Associated with neurodevelopmental disorder with hearing loss and spasticity.

What condition is associated with AFG2B p.Ser609Ter (c.1826C>G)?

AFG2B p.Ser609Ter (c.1826C>G) is associated with neurodevelopmental disorder with hearing loss and spasticity (ClinVar).

How common is AFG2B p.Ser609Ter (c.1826C>G) in the general population?

AFG2B p.Ser609Ter (c.1826C>G) is very rare (popmax 0.00134%, afr) (gnomAD).

AFG2B p.Ser609Ter

c.1826C>G · rs778481503 · VCV1275866

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

neurodevelopmental disorder with hearing loss and spasticity

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 8
REVEL	0.036	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.8	GERP 0.58, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,850 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000372% 6/1,613,314 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,466
African / African-Americangrpmax	0.00134%	74,850
European (non-Finnish)	0.000339%	294,925

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser609Ter
Coding: c.1826C>G
MANE Select: NM_024063
dbSNP: rs778481503
Type: single nucleotide variant
Location: chr15:45415768 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 2 PDB
Residue 609: a UniProt-annotated variant site (in nedhls)

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-ser609ter (accessed [today's date]).

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