Is FXN p.Pro16Ser (c.46C>T) pathogenic?

FXN p.Pro16Ser (c.46C>T) is classified Uncertain significance in FXN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-08). AlphaMissense: likely benign (0.0682); Very rare (popmax 0.00258%, eas); Associated with Inborn genetic diseases.

What condition is associated with FXN p.Pro16Ser (c.46C>T)?

FXN p.Pro16Ser (c.46C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FXN p.Pro16Ser (c.46C>T) in the general population?

FXN p.Pro16Ser (c.46C>T) is very rare (popmax 0.00258%, eas) (gnomAD).

What do computational predictors say about FXN p.Pro16Ser (c.46C>T)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

FXN p.Pro16Ser

c.46C>T · rs1392880712 · VCV2300251

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00258%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.275	benign-leaning
SaProt	LLR -5.88	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 -1.2	GERP -1.2
Regional constraint	o/e 0.99	unconstrained · MANE · 37 kb · p 0.93 · regional, not allelic
Overall
CADD	0.556	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 0.00258% East Asian · 1/38,692 alleles

Overall 0.000132% 2/1,513,046 alleles · very rare exomes 2/1,360,888 · genomes 0/152,158 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00258%	38,692
European (non-Finnish)	8.79e-05%	1,137,521

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: FXN
Protein: p.Pro16Ser
Coding: c.46C>T
MANE Select: NM_000144
dbSNP: rs1392880712
Type: single nucleotide variant
Location: chr9:69035828 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 75.93 · 19 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FXN p.Arg43His Uncertain significance ★★ ⚠ same condition
FXN p.Gly138Arg Uncertain significance ★★ ⚠ same condition
FXN p.Leu24Phe Uncertain significance ★★ ⚠ same condition
FXN p.Pro30Thr Uncertain significance ★★ ⚠ same condition
FXN p.Thr49Asn Uncertain significance ★★ ⚠ same condition
FXN p.Arg54= Benign/Likely benign ★★ same condition
FXN p.Asp178= Benign/Likely benign ★★ same condition
FXN p.Asp209Gly Benign/Likely benign ★★ 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/fxn-p-pro16ser (accessed [today's date]).

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