Is AFG2A p.Lys5Arg (c.14A>G) pathogenic?

AFG2A p.Lys5Arg (c.14A>G) is classified Uncertain significance in AFG2A (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-10). AlphaMissense: likely benign (0.0983); Very rare (popmax 0.000169%, nfe).

How common is AFG2A p.Lys5Arg (c.14A>G) in the general population?

AFG2A p.Lys5Arg (c.14A>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about AFG2A p.Lys5Arg (c.14A>G)?

AlphaMissense predicts likely benign (score 0.0983) — an in-silico prediction, not a clinical call.

AFG2A p.Lys5Arg

c.14A>G · rs1578507400 · VCV805522

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0983 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0983	likely benign
REVEL	0.426	indeterminate
SaProt	LLR -6.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 0.61, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 105 kb · p 0.81 · regional, not allelic
Overall
CADD	25.1	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 0.000169% European (non-Finnish) · 2/1,180,042 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,892 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.Lys5Arg
Coding: c.14A>G
MANE Select: NM_145207
dbSNP: rs1578507400
Type: single nucleotide variant
Location: chr4:122923156 (GRCh38)
Structure: AlphaFold pLDDT 73.21 · 2 PDB
Residue 5: the 'required for interaction with afg2b and cinp' region; the 'disordered' region

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

Similar variants

AFG2A p.Lys5Asn Uncertain significance ★ ⚠ same residue
AFG2A p.Lys5Glu Uncertain significance ★ ⚠ same residue
AFG2A p.Lys5Met Uncertain significance ★ ⚠ same residue
AFG2A p.Lys5= Likely benign ★ same residue
AFG2A p.Lys5del Uncertain significance ★ same residue
AFG2A c.1714+1G>A Pathogenic ★★ same type
AFG2A c.446+1G>A Likely pathogenic ★★ same type
AFG2A p.Ala844Val 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-lys5arg (accessed [today's date]).

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