Is ZFR p.Val561= (c.1683G>A) pathogenic?

ZFR p.Val561= (c.1683G>A) is classified Likely benign in ZFR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-03). Very rare (popmax 0.00336%, amr); Associated with Pure or complex autosomal recessive spastic paraplegia.

What condition is associated with ZFR p.Val561= (c.1683G>A)?

ZFR p.Val561= (c.1683G>A) is associated with Pure or complex autosomal recessive spastic paraplegia (ClinVar).

How common is ZFR p.Val561= (c.1683G>A) in the general population?

ZFR p.Val561= (c.1683G>A) is very rare (popmax 0.00336%, amr) (gnomAD).

ZFR p.Val561=

c.1683G>A · rs745790540 · VCV1667107

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00336%, amr)

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 -3	GERP -4
Overall
CADD	5.107	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00336% Admixed American · 2/59,444 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00224% 36/1,610,220 alleles · very rare exomes 33/1,458,034 · genomes 3/152,186 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00336%	29,722
European (non-Finnish)	0.0028%	35,709
Remaining individualsnot grpmax-eligible	0.0016%	62,308

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.Val561=
Coding: c.1683G>A
MANE Select: NM_016107
dbSNP: rs745790540
Type: single nucleotide variant
Location: chr5:32400037 (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.Val561Met Uncertain significance ★ ⚠ same residue
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

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-val561 (accessed [today's date]).

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