Is AFG3L2 p.Phe65Leu (c.195C>G) pathogenic?

AFG3L2 p.Phe65Leu (c.195C>G) is classified Uncertain significance in AFG3L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-08-27). AlphaMissense: likely benign (0.3225); Very rare (popmax 0.000137%).

How common is AFG3L2 p.Phe65Leu (c.195C>G) in the general population?

AFG3L2 p.Phe65Leu (c.195C>G) is very rare (popmax 0.000137%) (gnomAD).

What do computational predictors say about AFG3L2 p.Phe65Leu (c.195C>G)?

AlphaMissense predicts likely benign (score 0.3225) — an in-silico prediction, not a clinical call.

AFG3L2 p.Phe65Leu

c.195C>G · rs1908993127 · VCV1051388

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3225 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000137%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3225	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -6.45	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 2.5	GERP -0.62, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 10 kb · p 0.13 · regional, not allelic
Overall
CADD	14.33	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 0.000137%

Overall 0.000137% 2/1,461,634 alleles · very rare

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.Phe65Leu
Coding: c.195C>G
MANE Select: NM_006796
dbSNP: rs1908993127
Type: single nucleotide variant
Location: chr18:12371611 (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.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-phe65leu (accessed [today's date]).

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