Is AFG2A p.Glu696Asp (c.2088A>C) pathogenic?

AFG2A p.Glu696Asp (c.2088A>C) is classified Uncertain significance in AFG2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-26). AlphaMissense: likely pathogenic (0.582); Ultra-rare (popmax 0.0287%, sas); Associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

How common is AFG2A p.Glu696Asp (c.2088A>C) in the general population?

AFG2A p.Glu696Asp (c.2088A>C) is ultra-rare (popmax 0.0287%, sas) (gnomAD).

What do computational predictors say about AFG2A p.Glu696Asp (c.2088A>C)?

AlphaMissense predicts likely pathogenic (score 0.582) — an in-silico prediction, not a clinical call.

AFG2A p.Glu696Asp

Q: What condition is associated with AFG2A p.Glu696Asp (c.2088A>C)?

AFG2A p.Glu696Asp (c.2088A>C) is associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

c.2088A>C · rs376160539 · VCV858797

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.582 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0287%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.582	likely pathogenic
REVEL	0.642	indeterminate
SaProt	LLR -12.07	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 0.095	GERP 1.5, phastCons 0.013
Regional constraint	o/e 0.67	unconstrained · MANE · 62 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0287% South Asian · 26/90,654 alleles

Filtering AF 0.02% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00219% 32/1,459,944 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0287%	3,487
Remaining individualsnot grpmax-eligible	0.00962%	10,400

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.Glu696Asp
Coding: c.2088A>C
MANE Select: NM_145207
dbSNP: rs376160539
Type: single nucleotide variant
Location: chr4:123056395 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 696: 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.1714+1G>A Pathogenic ★★ same condition
AFG2A c.446+1G>A Likely pathogenic ★★ same condition
AFG2A p.Ala844Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
AFG2A p.Arg445Ter Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Arg510Ter Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Arg514Ter Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Arg538Ter Pathogenic/Likely pathogenic ★★ same condition
AFG2A p.Arg655Ter Pathogenic/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-glu696asp (accessed [today's date]).

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