Is AFG2A p.Ala682Val (c.2045C>T) pathogenic?

AFG2A p.Ala682Val (c.2045C>T) is classified Likely pathogenic in AFG2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely pathogenic (0.724); Very rare (popmax 0.0022%, sas).

How common is AFG2A p.Ala682Val (c.2045C>T) in the general population?

AFG2A p.Ala682Val (c.2045C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about AFG2A p.Ala682Val (c.2045C>T)?

AlphaMissense predicts likely pathogenic (score 0.724) — an in-silico prediction, not a clinical call.

AFG2A p.Ala682Val

c.2045C>T · rs866943725 · VCV1197811

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.724 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.724	likely pathogenic ✓ concordant with ClinVar
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -14.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 62 kb · p 7.1e-05 · regional, not allelic
Overall
CADD	27.6	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 0.0022% South Asian · 2/91,088 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000434% 7/1,613,980 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,544
European (non-Finnish)	0.000424%	236,000

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.Ala682Val
Coding: c.2045C>T
MANE Select: NM_145207
dbSNP: rs866943725
Type: single nucleotide variant
Location: chr4:123028361 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 682: a UniProt-annotated variant site (in nedhsb)

Full AFG2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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AFG2A c.446+1G>A Likely pathogenic ★★ same type
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AFG2A p.Arg445Ter Pathogenic/Likely pathogenic ★★ same type
AFG2A p.Arg510Ter Pathogenic/Likely pathogenic ★★ same type
AFG2A p.Arg514Ter Pathogenic/Likely pathogenic ★★ same type
AFG2A p.Arg538Ter Pathogenic/Likely pathogenic ★★ same type
AFG2A p.Arg655Ter Pathogenic/Likely pathogenic ★★ same type

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-ala682val (accessed [today's date]).

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