Is DDHD1 p.Ala68= (c.204G>A) pathogenic?

DDHD1 p.Ala68= (c.204G>A) is classified Likely benign in DDHD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-07). Rare (popmax 0.103%, afr); Associated with hereditary spastic paraplegia 28.

What condition is associated with DDHD1 p.Ala68= (c.204G>A)?

DDHD1 p.Ala68= (c.204G>A) is associated with hereditary spastic paraplegia 28 (ClinVar).

How common is DDHD1 p.Ala68= (c.204G>A) in the general population?

DDHD1 p.Ala68= (c.204G>A) is rare (popmax 0.103%, afr) (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.Ala68=

c.204G>A · rs139727469 · VCV382070

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.103%, afr)

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 -0.3	GERP -0.5, phastCons 0.24
Overall
CADD	9.955	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.103% African / African-American · 77/74,708 alleles

Filtering AF 0.0844% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0777%

Overall 0.00497% 80/1,608,522 alleles · rare exomes 36/1,456,376 · genomes 44/152,146 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.103%	970
Remaining individualsnot grpmax-eligible	0.00322%	31,095
European (non-Finnish)	8.49e-05%	1,177,802

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.Ala68=
Coding: c.204G>A
MANE Select: NM_001160148
dbSNP: rs139727469
Type: single nucleotide variant
Location: chr14:53152895 (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.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-ala68 (accessed [today's date]).

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