Is AFG3L2 p.Phe377Ser (c.1130T>C) pathogenic?

AFG3L2 p.Phe377Ser (c.1130T>C) is classified Likely pathogenic in AFG3L2 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-02-12). AlphaMissense: likely pathogenic (0.9988); Absent from gnomAD v4.1; Associated with optic nerve disorder.

What condition is associated with AFG3L2 p.Phe377Ser (c.1130T>C)?

AFG3L2 p.Phe377Ser (c.1130T>C) is associated with optic nerve disorder, optic atrophy (ClinVar).

How common is AFG3L2 p.Phe377Ser (c.1130T>C) in the general population?

AFG3L2 p.Phe377Ser (c.1130T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AFG3L2 p.Phe377Ser (c.1130T>C)?

AlphaMissense predicts likely pathogenic (score 0.9988) — an in-silico prediction, not a clinical call.

AFG3L2 p.Phe377Ser

c.1130T>C · rs1908507433 · VCV973110

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9988 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

optic nerve disorder

Computational evidence

Protein change
AlphaMissense	0.9988	likely pathogenic ✓ concordant with ClinVar · top 5% in AFG3L2
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -15.50	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 7,589 bp · p 4.6e-15 · regional, not allelic
Overall
CADD	29.6	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

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.Phe377Ser
Coding: c.1130T>C
MANE Select: NM_006796
dbSNP: rs1908507433
Type: single nucleotide variant
Location: chr18:12356728 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.07 · 2 PDB
Residue 377: a UniProt-annotated variant site (in opa12; uncertain significance)

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

Disease context

optic nerve disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: optic atrophy

Similar variants

AFG3L2 p.Arg468Cys Pathogenic/Likely pathogenic ★★ same condition
AFG3L2 p.Asp407Gly Likely pathogenic ★ same condition
AFG3L2 p.Ala462Val Conflicting classifications of pathogenicity ★ ⚠ same condition
AFG3L2 p.Thr355Met Conflicting classifications of pathogenicity ★ ⚠ same condition
AFG3L2 p.Arg465Lys Pathogenic same condition
AFG3L2 p.Leu346Phe Pathogenic same condition
AFG3L2 p.Pro514Leu Pathogenic same condition
AFG3L2 p.Thr430Ile Pathogenic 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/afg3l2-p-phe377ser (accessed [today's date]).

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