Is AFG2B p.Pro558Arg (c.1673C>G) pathogenic?

AFG2B p.Pro558Arg (c.1673C>G) is classified Uncertain significance in AFG2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-09). AlphaMissense: ambiguous (0.4824); Very rare (popmax 0.00401%, afr); Associated with Inborn genetic diseases.

What condition is associated with AFG2B p.Pro558Arg (c.1673C>G)?

AFG2B p.Pro558Arg (c.1673C>G) is associated with Inborn genetic diseases (ClinVar).

How common is AFG2B p.Pro558Arg (c.1673C>G) in the general population?

AFG2B p.Pro558Arg (c.1673C>G) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about AFG2B p.Pro558Arg (c.1673C>G)?

AlphaMissense predicts ambiguous (score 0.4824) — an in-silico prediction, not a clinical call.

AFG2B p.Pro558Arg

c.1673C>G · rs750709908 · VCV2364794

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4824	ambiguous
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -14.45	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 19 kb · p 0.58 · regional, not allelic
Overall
CADD	26.7	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 0.00401% African / African-American · 3/74,834 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00223% 36/1,613,800 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,945
European (non-Finnish)	0.00271%	36,874
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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: AFG2B
Protein: p.Pro558Arg
Coding: c.1673C>G
MANE Select: NM_024063
dbSNP: rs750709908
Type: single nucleotide variant
Location: chr15:45415615 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 2 PDB

Full AFG2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AFG2B p.Pro558Ala Uncertain significance ★ ⚠ same residue
AFG2B p.Arg28Cys Uncertain significance ★★ ⚠ same condition
AFG2B p.Ser333Ile Uncertain significance ★★ ⚠ same condition
AFG2B p.Tyr738Cys Uncertain significance ★★ ⚠ same condition
AFG2B p.Ala130Thr Uncertain significance ★ ⚠ same condition
AFG2B p.Ala130Val Uncertain significance ★ ⚠ same condition
AFG2B p.Ala135Thr Uncertain significance ★ ⚠ same condition
AFG2B p.Ala156Ser Uncertain significance ★ ⚠ 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/afg2b-p-pro558arg (accessed [today's date]).

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