Is AFG2A p.Arg577Gln (c.1730G>A) pathogenic?

AFG2A p.Arg577Gln (c.1730G>A) is classified Uncertain significance in AFG2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). AlphaMissense: likely benign (0.0809); Very rare (popmax 0.00549%, sas); Associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

How common is AFG2A p.Arg577Gln (c.1730G>A) in the general population?

AFG2A p.Arg577Gln (c.1730G>A) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about AFG2A p.Arg577Gln (c.1730G>A)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

AFG2A p.Arg577Gln

Q: What condition is associated with AFG2A p.Arg577Gln (c.1730G>A)?

AFG2A p.Arg577Gln (c.1730G>A) is associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

c.1730G>A · rs754575085 · VCV944965

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.637	indeterminate
SaProt	LLR -10.82	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP -0.36, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 105 kb · p 0.81 · regional, not allelic
Overall
CADD	23.6	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 0.00549% South Asian · 5/91,054 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000867% 14/1,613,966 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,211
Admixed American	0.00333%	29,999
Finnishnot grpmax-eligible	0.00312%	32,019
East Asian	0.00223%	44,886
African / African-American	0.00133%	74,928
European (non-Finnish)	0.000254%	393,332

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.Arg577Gln
Coding: c.1730G>A
MANE Select: NM_145207
dbSNP: rs754575085
Type: single nucleotide variant
Location: chr4:122979247 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 577: 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.Arg577Trp 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-arg577gln (accessed [today's date]).

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