Is DDHD1 p.Pro722= (c.2166A>G) pathogenic?

DDHD1 p.Pro722= (c.2166A>G) is classified Likely benign in DDHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 28.

What condition is associated with DDHD1 p.Pro722= (c.2166A>G)?

DDHD1 p.Pro722= (c.2166A>G) is associated with hereditary spastic paraplegia 28 (ClinVar).

How common is DDHD1 p.Pro722= (c.2166A>G) in the general population?

DDHD1 p.Pro722= (c.2166A>G) is absent from gnomAD v4.1 (gnomAD).

How is Autosomal recessive spastic paraplegia type 28 inherited?

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

DDHD1 p.Pro722=

c.2166A>G · rs2139839870 · VCV1083750

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary spastic paraplegia 28

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 -0.83	GERP -2.2, phastCons 0.008
Overall
CADD	6.354	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DDHD1
Protein: p.Pro722=
Coding: c.2166A>G
MANE Select: NM_001160148
dbSNP: rs2139839870
Type: single nucleotide variant
Location: chr14:53055739 (GRCh38)
Gene constraint: LOEUF 0.642 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 67.11
Residue 722: the ddhd domain; the 'disordered' region

Full DDHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 28 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 28 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood, Infancy

Similar variants

DDHD1 p.Ala193Val Uncertain significance ★★ ⚠ same condition
DDHD1 p.Ala94Pro Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg204Trp Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg288His Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg554Gln Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg570Gln Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg588Gln Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg596Gln 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/ddhd1-p-pro722 (accessed [today's date]).

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