Is AFG2A p.Val560Ile (c.1678G>A) pathogenic?

AFG2A p.Val560Ile (c.1678G>A) is classified Conflicting classifications of pathogenicity in AFG2A (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-08-27). AlphaMissense: likely benign (0.2147); Very rare (popmax 0.00167%, amr); Associated with syndromic complex neurodevelopmental disorder.

What condition is associated with AFG2A p.Val560Ile (c.1678G>A)?

AFG2A p.Val560Ile (c.1678G>A) is associated with syndromic complex neurodevelopmental disorder, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

How common is AFG2A p.Val560Ile (c.1678G>A) in the general population?

AFG2A p.Val560Ile (c.1678G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Non-specific syndromic intellectual disability inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AFG2A p.Val560Ile (c.1678G>A)?

AlphaMissense predicts likely benign (score 0.2147) — an in-silico prediction, not a clinical call.

AFG2A p.Val560Ile

c.1678G>A · rs756560225 · VCV1393086

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2147 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

syndromic complex neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.2147	likely benign
REVEL	0.735	pathogenic-leaning
SaProt	LLR -10.61	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 105 kb · p 0.81 · regional, not allelic
Overall
CADD	25.0	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 0.00167% Admixed American · 1/59,958 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,548 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,958
European (non-Finnish)	0.000254%	393,232

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.Val560Ile
Coding: c.1678G>A
MANE Select: NM_145207
dbSNP: rs756560225
Type: single nucleotide variant
Location: chr4:122947452 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 560: a UniProt-annotated variant site (in nedhsb)

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

Disease context

syndromic complex neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Non-specific syndromic intellectual disability (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Childhood, Infancy

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-val560ile (accessed [today's date]).

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