Is AFG2A p.Arg436Cys (c.1306C>T) pathogenic?

AFG2A p.Arg436Cys (c.1306C>T) is classified Uncertain significance in AFG2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-23). AlphaMissense: ambiguous (0.5154); Very rare (popmax 0.00338%, sas); Associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

How common is AFG2A p.Arg436Cys (c.1306C>T) in the general population?

AFG2A p.Arg436Cys (c.1306C>T) is very rare (popmax 0.00338%, sas) (gnomAD).

What do computational predictors say about AFG2A p.Arg436Cys (c.1306C>T)?

AlphaMissense predicts ambiguous (score 0.5154) — an in-silico prediction, not a clinical call.

AFG2A p.Arg436Cys

Q: What condition is associated with AFG2A p.Arg436Cys (c.1306C>T)?

AFG2A p.Arg436Cys (c.1306C>T) is associated with microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (ClinVar).

c.1306C>T · rs1247048378 · VCV963121

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5154 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00338%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.5154	ambiguous
REVEL	0.889	moderately pathogenic-leaning
SaProt	LLR -15.07	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.46 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.3	GERP 1.3, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 105 kb · p 0.81 · regional, not allelic
Overall
CADD	33.0	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 0.00338% South Asian · 3/88,664 alleles

Filtering AF 0.000899% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000449%

Overall 0.000561% 9/1,603,948 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00338%	29,555
Remaining individualsnot grpmax-eligible	0.00161%	62,022
European (non-Finnish)	0.000425%	235,049

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.Arg436Cys
Coding: c.1306C>T
MANE Select: NM_145207
dbSNP: rs1247048378
Type: single nucleotide variant
Location: chr4:122936128 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 436: 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.Arg436His 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-arg436cys (accessed [today's date]).

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