Is PRX p.Pro1166Ser (c.3496C>T) pathogenic?

PRX p.Pro1166Ser (c.3496C>T) is classified Conflicting classifications of pathogenicity in PRX (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.0607); Rare (popmax 0.445%, mid); Associated with Inborn genetic diseases.

What condition is associated with PRX p.Pro1166Ser (c.3496C>T)?

PRX p.Pro1166Ser (c.3496C>T) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease type 4F, Charcot-Marie-Tooth disease (ClinVar).

How common is PRX p.Pro1166Ser (c.3496C>T) in the general population?

PRX p.Pro1166Ser (c.3496C>T) is rare (popmax 0.445%, mid) (gnomAD).

What do computational predictors say about PRX p.Pro1166Ser (c.3496C>T)?

AlphaMissense predicts likely benign (score 0.0607) — an in-silico prediction, not a clinical call.

PRX p.Pro1166Ser

c.3496C>T · rs147826200 · VCV216835

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0607 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.445%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0607	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -6.43	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 0.42	GERP -2.7
Regional constraint	o/e 0.96	unconstrained · MANE · 2,740 bp · p 0.15 · regional, not allelic
Overall
CADD	0.122	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 0.445% Middle Eastern · 27/6,062 alleles

Filtering AF 0.314% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.27%

Overall 0.108% 1,744/1,612,330 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.445%	225
European (non-Finnish)	0.129%	773
Admixed American	0.113%	883
Remaining individualsnot grpmax-eligible	0.0912%	1,096
South Asian	0.0351%	2,846
African / African-American	0.032%	3,126
Finnishnot grpmax-eligible	0.0144%	6,921
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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: PRX
Protein: p.Pro1166Ser
Coding: c.3496C>T
MANE Select: NM_181882
dbSNP: rs147826200
Type: single nucleotide variant
Location: chr19:40394856 (GRCh38)
Gene constraint: LOEUF 1.321 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 35.74 · 1 PDB

Full PRX 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

Also linked: Charcot-Marie-Tooth disease type 4F Charcot-Marie-Tooth disease Charcot-Marie-Tooth disease type 4

Similar variants

PRX c.184+2T>C Likely pathogenic ★★ same condition
PRX p.Arg1070Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Arg196Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Arg364Ter Pathogenic ★★ same condition
PRX p.Arg368Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Arg392Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Arg464Ter Pathogenic/Likely pathogenic ★★ same condition
PRX p.Arg897Ter Pathogenic/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/prx-p-pro1166ser (accessed [today's date]).

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