Is DDHD1 p.Val349fs (c.1044dup) pathogenic?

DDHD1 p.Val349fs (c.1044dup) is classified Pathogenic in DDHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-19). Very rare (popmax 0.00167%, amr); Associated with hereditary spastic paraplegia 28.

What condition is associated with DDHD1 p.Val349fs (c.1044dup)?

DDHD1 p.Val349fs (c.1044dup) is associated with hereditary spastic paraplegia 28 (ClinVar).

How common is DDHD1 p.Val349fs (c.1044dup) in the general population?

DDHD1 p.Val349fs (c.1044dup) is very rare (popmax 0.00167%, amr) (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.Val349fs

c.1044dup · rs1886604612 · VCV951954

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

hereditary spastic paraplegia 28

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,712 alleles

Overall 6.2e-05% 1/1,612,146 alleles · very rare exomes 1/1,459,858 · genomes 0/152,288 · joint denominator

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: DDHD1
Protein: p.Val349fs
Coding: c.1044dup
MANE Select: NM_001160148
dbSNP: rs1886604612
Type: Duplication
Location: chr14:53093412 (GRCh38)
Gene constraint: LOEUF 0.642 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 67.11

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.Gly133fs Pathogenic ★★ same condition
DDHD1 p.Ser108_Gly109dup Uncertain significance ★★ same condition
DDHD1 c.1993-19dup Benign/Likely benign ★★ same condition
DDHD1 p.Asn2fs Pathogenic ★ same condition
DDHD1 p.Leu115fs Pathogenic ★ same condition
DDHD1 p.Pro609fs Pathogenic ★ same condition
DDHD1 c.1993-6dup Likely benign ★ same condition
DDHD1 p.Met547Ter 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/ddhd1-p-val349fs (accessed [today's date]).

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