Is AFG3L2 p.Glu575Asp (c.1725A>T) pathogenic?

AFG3L2 p.Glu575Asp (c.1725A>T) is classified Uncertain significance in AFG3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-20). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1.

How common is AFG3L2 p.Glu575Asp (c.1725A>T) in the general population?

AFG3L2 p.Glu575Asp (c.1725A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AFG3L2 p.Glu575Asp (c.1725A>T)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

AFG3L2 p.Glu575Asp

c.1725A>T · rs2510223792 · VCV2574805

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic · top 2% in AFG3L2
REVEL	0.882	moderately pathogenic-leaning
SaProt	LLR -14.24	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 0.024	GERP -1.5, phastCons 0.92
Regional constraint	o/e 0.74	unconstrained · MANE · 22 kb · p 3e-07 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AFG3L2
Protein: p.Glu575Asp
Coding: c.1725A>T
MANE Select: NM_006796
dbSNP: rs2510223792
Type: single nucleotide variant
Location: chr18:12344186 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.07 · 2 PDB
Residue 575: an α-helix; an active site

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

Similar variants

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
AFG3L2 p.Met666Thr Pathogenic/Likely pathogenic ★★ same type
AFG3L2 p.Met666Val 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/afg3l2-p-glu575asp (accessed [today's date]).

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