Is AFG2B p.Pro673Leu (c.2018C>T) pathogenic?

AFG2B p.Pro673Leu (c.2018C>T) is classified Uncertain significance in AFG2B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-13). AlphaMissense: likely benign (0.0732); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with AFG2B p.Pro673Leu (c.2018C>T)?

AFG2B p.Pro673Leu (c.2018C>T) is associated with Inborn genetic diseases (ClinVar).

How common is AFG2B p.Pro673Leu (c.2018C>T) in the general population?

AFG2B p.Pro673Leu (c.2018C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about AFG2B p.Pro673Leu (c.2018C>T)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

AFG2B p.Pro673Leu

c.2018C>T · VCV3504529

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.178	moderately benign-leaning
SaProt	LLR -7.96	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 1.7	GERP 1.8, phastCons 0.003
Regional constraint	o/e 0.98	unconstrained · MANE · 19 kb · p 0.58 · regional, not allelic
Overall
CADD	17.85	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 0.0107% African / African-American · 8/74,882 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000558% 9/1,613,854 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,360
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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.Pro673Leu
Coding: c.2018C>T
MANE Select: NM_024063
Type: single nucleotide variant
Location: chr15:45418606 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 2 PDB
Residue 673: a UniProt-annotated variant site (in nedhls)

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.Pro673Ser Uncertain significance ★ ⚠ same residue
AFG2B p.Arg28Cys Uncertain significance ★★ ⚠ same condition
AFG2B p.Pro558Arg 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

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-pro673leu (accessed [today's date]).

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