Is AFG2A p.Glu640Gln (c.1918G>C) pathogenic?

AFG2A p.Glu640Gln (c.1918G>C) is classified Benign in AFG2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0458); Common (popmax 14.3%, sas) — too common for a highly-penetrant pathogenic allele; Associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

What do computational predictors say about AFG2A p.Glu640Gln (c.1918G>C)?

AlphaMissense predicts likely benign (score 0.0458) — an in-silico prediction, not a clinical call.

AFG2A p.Glu640Gln

Q: What condition is associated with AFG2A p.Glu640Gln (c.1918G>C)?

AFG2A p.Glu640Gln (c.1918G>C) is associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

Q: How common is AFG2A p.Glu640Gln (c.1918G>C) in the general population?

AFG2A p.Glu640Gln (c.1918G>C) is common (popmax 14.3%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1918G>C · rs35343500 · VCV475724

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0458 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 14.3%, sas) — too common for a highly-penetrant pathogenic allele

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	0.0458	likely benign
REVEL	0.255	benign-leaning
SaProt	LLR 1.10	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 9	GERP 0.57, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 105 kb · p 0.81 · regional, not allelic
Overall
CADD	20.0	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 14.3% South Asian · 13,003/91,072 alleles

Filtering AF 14.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 14%

Overall 2.72% 43,900/1,614,012 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	14.3%	7
Middle Eastern	6.07%	16
African / African-American	5.71%	18
Admixed American	4.94%	20
Ashkenazi Jewishnot grpmax-eligible	3.5%	29
Remaining individualsnot grpmax-eligible	3.21%	31
European (non-Finnish)	1.66%	60
East Asian	0.883%	113
Finnishnot grpmax-eligible	0.394%	254

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.Glu640Gln
Coding: c.1918G>C
MANE Select: NM_145207
dbSNP: rs35343500
Type: single nucleotide variant
Location: chr4:123028234 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 640: 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.Glu640Ala Benign ★ 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-glu640gln (accessed [today's date]).

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