Is AFG2A p.Lys349Arg (c.1046A>G) pathogenic?

AFG2A p.Lys349Arg (c.1046A>G) is classified Benign/Likely benign in AFG2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-11). AlphaMissense: likely benign (0.0672); Ultra-rare (popmax 0.033%, mid); Associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

How common is AFG2A p.Lys349Arg (c.1046A>G) in the general population?

AFG2A p.Lys349Arg (c.1046A>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about AFG2A p.Lys349Arg (c.1046A>G)?

AlphaMissense predicts likely benign (score 0.0672) — an in-silico prediction, not a clinical call.

AFG2A p.Lys349Arg

Q: What condition is associated with AFG2A p.Lys349Arg (c.1046A>G)?

AFG2A p.Lys349Arg (c.1046A>G) is associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

c.1046A>G · rs146372781 · VCV542391

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0672 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0672	likely benign
REVEL	0.224	benign-leaning
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.021	GERP -3.7, phastCons 0.039
Regional constraint	o/e 0.99	unconstrained · MANE · 105 kb · p 0.81 · regional, not allelic
Overall
CADD	13.68	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 0.033% Middle Eastern · 2/6,058 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.0384% 619/1,613,878 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.44%	70
Remaining individualsnot grpmax-eligible	0.117%	856
Middle Easterngrpmax	0.033%	3,029
Admixed American	0.0267%	3,748
European (non-Finnish)	0.00805%	12,421
South Asian	0.0055%	18,188
African / African-American	0.00267%	37,516
East Asian	0.00223%	44,870

Ashkenazi Jewish 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: AFG2A
Protein: p.Lys349Arg
Coding: c.1046A>G
MANE Select: NM_145207
dbSNP: rs146372781
Type: single nucleotide variant
Location: chr4:122934637 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 349: 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 p.Lys349Glu Uncertain significance ★ ⚠ same residue
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

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-lys349arg (accessed [today's date]).

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