Is FBXL4 p.Arg22Pro (c.65G>C) pathogenic?

FBXL4 p.Arg22Pro (c.65G>C) is classified Uncertain significance in FBXL4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-07-03). AlphaMissense: likely pathogenic (0.7363); Ultra-rare (popmax 0.0164%, mid); Associated with mitochondrial DNA depletion syndrome 13.

What condition is associated with FBXL4 p.Arg22Pro (c.65G>C)?

FBXL4 p.Arg22Pro (c.65G>C) is associated with mitochondrial DNA depletion syndrome 13 (ClinVar).

How common is FBXL4 p.Arg22Pro (c.65G>C) in the general population?

FBXL4 p.Arg22Pro (c.65G>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about FBXL4 p.Arg22Pro (c.65G>C)?

AlphaMissense predicts likely pathogenic (score 0.7363) — an in-silico prediction, not a clinical call.

FBXL4 p.Arg22Pro

Q: How is Mitochondrial DNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.65G>C · rs147696366 · VCV437527

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7363 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial DNA depletion syndrome 13

Computational evidence

Protein change
AlphaMissense	0.7363	likely pathogenic
REVEL	0.204	benign-leaning
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 53 kb · p 0.031 · regional, not allelic
Overall
CADD	23.2	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

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.0108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.00991% 160/1,613,950 alleles · ultra-rare exomes 151/1,461,854 · genomes 9/152,096 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,934
Middle Easterngrpmax	0.0164%	6,082
European (non-Finnish)	0.0125%	8,027
Remaining individualsnot grpmax-eligible	0.0048%	20,829
South Asian	0.0022%	45,535
Admixed American	0.00167%	59,984

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: FBXL4
Protein: p.Arg22Pro
Coding: c.65G>C
MANE Select: NM_001278716
dbSNP: rs147696366
Type: single nucleotide variant
Location: chr6:98926924 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.50

Full FBXL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial DNA depletion syndrome 13 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mitochondrial DNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

FBXL4 p.Arg22Ter Pathogenic/Likely pathogenic ★★ same residue
FBXL4 p.Arg22Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
FBXL4 c.859-1G>T Pathogenic/Likely pathogenic ★★ same condition
FBXL4 p.Arg206Ter Pathogenic/Likely pathogenic ★★ same condition
FBXL4 p.Arg36Ter Pathogenic ★★ same condition
FBXL4 p.Arg430Ter Pathogenic/Likely pathogenic ★★ same condition
FBXL4 p.Arg435Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
FBXL4 p.Arg435Leu Likely 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/fbxl4-p-arg22pro (accessed [today's date]).

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