Is ZFR p.Pro229= (c.687T>A) pathogenic?

ZFR p.Pro229= (c.687T>A) is classified Likely benign in ZFR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-20). Ultra-rare (popmax 0.02%, afr); Associated with Pure or complex autosomal recessive spastic paraplegia.

What condition is associated with ZFR p.Pro229= (c.687T>A)?

ZFR p.Pro229= (c.687T>A) is associated with Pure or complex autosomal recessive spastic paraplegia (ClinVar).

How common is ZFR p.Pro229= (c.687T>A) in the general population?

ZFR p.Pro229= (c.687T>A) is ultra-rare (popmax 0.02%, afr) (gnomAD).

ZFR p.Pro229=

c.687T>A · rs546731156 · VCV2738850

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Conditions

Pure or complex autosomal recessive spastic paraplegia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.29, phastCons 1
Overall
CADD	11.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% African / African-American · 15/75,042 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00987%

Overall 0.00192% 31/1,614,146 alleles · ultra-rare exomes 21/1,461,848 · genomes 10/152,298 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.02%	5,003
Middle Eastern	0.0165%	6,062
Admixed American	0.00167%	60,016
Remaining individualsnot grpmax-eligible	0.0016%	62,500
European (non-Finnish)	0.0011%	90,770

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: ZFR
Protein: p.Pro229=
Coding: c.687T>A
MANE Select: NM_016107
dbSNP: rs546731156
Type: single nucleotide variant
Location: chr5:32415066 (GRCh38)
Gene constraint: LOEUF 0.219 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.11

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

Disease context

Pure or complex autosomal recessive spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ZFR p.Ala833Gly Uncertain significance ★★ ⚠ same condition
ZFR p.Arg669Lys Uncertain significance ★★ ⚠ same condition
ZFR p.Arg681His Uncertain significance ★★ ⚠ same condition
ZFR p.Arg915Lys Uncertain significance ★★ ⚠ same condition
ZFR p.Asn595Ser Uncertain significance ★★ ⚠ same condition
ZFR p.Ile1026Val Uncertain significance ★★ ⚠ same condition
ZFR p.Lys830Glu Uncertain significance ★★ ⚠ same condition
ZFR p.Met1038Ile Uncertain significance ★★ ⚠ 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/zfr-p-pro229 (accessed [today's date]).

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