Is AFG2A p.Leu536fs (c.1607del) pathogenic?

AFG2A p.Leu536fs (c.1607del) is classified Pathogenic in AFG2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-01). Very rare (popmax 0.000678%, nfe); Associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

How common is AFG2A p.Leu536fs (c.1607del) in the general population?

AFG2A p.Leu536fs (c.1607del) is very rare (popmax 0.000678%, nfe) (gnomAD).

AFG2A p.Leu536fs

Q: What condition is associated with AFG2A p.Leu536fs (c.1607del)?

AFG2A p.Leu536fs (c.1607del) is associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

c.1607del · rs1730087475 · VCV1695107

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Conditions

microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.1	GERP -0.086, phastCons 0.99
Overall
CADD	32.0	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 0.000678% European (non-Finnish) · 8/1,180,008 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,956 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: AFG2A
Protein: p.Leu536fs
Coding: c.1607del
MANE Select: NM_145207
dbSNP: rs1730087475
Type: Deletion
Location: chr4:122947381 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 536: a UniProt-annotated variant site (in nedhsb)

Full AFG2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AFG2A c.1147+1_1147+5del Likely pathogenic ★★ same condition
AFG2A p.Ala742fs Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Asn525fs Pathogenic ★★ same condition
AFG2A p.Gly357_Leu358insTer Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Pro669fs Pathogenic ★★ same condition
AFG2A c.1334+6_1334+9del Likely benign ★★ same condition
AFG2A c.1459-17del Benign/Likely benign ★★ same condition
AFG2A c.1459-11_1478del 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/afg2a-p-leu536fs (accessed [today's date]).

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