Is AFG3L2 p.Arg11Pro (c.32G>C) pathogenic?

AFG3L2 p.Arg11Pro (c.32G>C) is classified Uncertain significance in AFG3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-19). AlphaMissense: likely benign (0.093); Very rare (popmax 0.00297%, afr).

How common is AFG3L2 p.Arg11Pro (c.32G>C) in the general population?

AFG3L2 p.Arg11Pro (c.32G>C) is very rare (popmax 0.00297%, afr) (gnomAD).

What do computational predictors say about AFG3L2 p.Arg11Pro (c.32G>C)?

AlphaMissense predicts likely benign (score 0.093) — an in-silico prediction, not a clinical call.

AFG3L2 p.Arg11Pro

c.32G>C · rs1275518816 · VCV2724362

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.093 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00297%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.093	likely benign
REVEL	0.477	indeterminate
SaProt	LLR -8.20	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 4.1	GERP 1, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 10 kb · p 0.13 · regional, not allelic
Overall
CADD	19.99	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 0.00297% African / African-American · 2/67,400 alleles

Filtering AF 0.000492% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000184%

Overall 0.000209% 3/1,435,752 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00297%	33,700
Admixed American	0.00256%	39,124

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: AFG3L2
Protein: p.Arg11Pro
Coding: c.32G>C
MANE Select: NM_006796
dbSNP: rs1275518816
Type: single nucleotide variant
Location: chr18:12377051 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.07 · 2 PDB

Full AFG3L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFG3L2 p.Arg11Gly Uncertain significance ★★ ⚠ same residue
AFG3L2 p.Arg11Trp Uncertain significance ★ ⚠ same residue
AFG3L2 p.Arg41Ter Pathogenic/Likely pathogenic ★★ same type
AFG3L2 p.Arg468Cys Pathogenic/Likely pathogenic ★★ same type
AFG3L2 p.Arg68Ter Pathogenic ★★ same type
AFG3L2 p.Gly337Glu Pathogenic ★★ same type
AFG3L2 p.Gly385Ser Likely pathogenic ★★ same type
AFG3L2 p.Gly671Arg 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/afg3l2-p-arg11pro (accessed [today's date]).

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