Is AFG2A p.Ala504Ser (c.1510G>T) pathogenic?

AFG2A p.Ala504Ser (c.1510G>T) is classified Uncertain significance in AFG2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-08). AlphaMissense: likely benign (0.0813); Very rare (popmax 0.000254%, nfe); Associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

How common is AFG2A p.Ala504Ser (c.1510G>T) in the general population?

AFG2A p.Ala504Ser (c.1510G>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about AFG2A p.Ala504Ser (c.1510G>T)?

AlphaMissense predicts likely benign (score 0.0813) — an in-silico prediction, not a clinical call.

AFG2A p.Ala504Ser

Q: What condition is associated with AFG2A p.Ala504Ser (c.1510G>T)?

AFG2A p.Ala504Ser (c.1510G>T) is associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

c.1510G>T · rs774842837 · VCV2123003

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0813 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

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	0.0813	likely benign
REVEL	0.214	benign-leaning
SaProt	LLR -6.72	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 4.2	GERP -0.33, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 105 kb · p 0.81 · regional, not allelic
Overall
CADD	19.34	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000254% European (non-Finnish) · 3/1,178,840 alleles

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

Overall 0.000205% 3/1,459,998 alleles · very rare

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.Ala504Ser
Coding: c.1510G>T
MANE Select: NM_145207
dbSNP: rs774842837
Type: single nucleotide variant
Location: chr4:122947284 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 504: 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.Ala504Asp 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-ala504ser (accessed [today's date]).

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