Is DDHD2 p.Ser129Leu (c.386C>T) pathogenic?

DDHD2 p.Ser129Leu (c.386C>T) is classified Uncertain significance in DDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-10). AlphaMissense: likely benign (0.1192); Very rare (popmax 0.00492%, nfe); Associated with hereditary spastic paraplegia 54.

What condition is associated with DDHD2 p.Ser129Leu (c.386C>T)?

DDHD2 p.Ser129Leu (c.386C>T) is associated with hereditary spastic paraplegia 54 (ClinVar).

How common is DDHD2 p.Ser129Leu (c.386C>T) in the general population?

DDHD2 p.Ser129Leu (c.386C>T) is very rare (popmax 0.00492%, nfe) (gnomAD).

How is Autosomal recessive spastic paraplegia type 54 inherited?

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

What do computational predictors say about DDHD2 p.Ser129Leu (c.386C>T)?

AlphaMissense predicts likely benign (score 0.1192) — an in-silico prediction, not a clinical call.

DDHD2 p.Ser129Leu

c.386C>T · rs748398783 · VCV2040339

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1192 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00492%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 54

Computational evidence

Protein change
AlphaMissense	0.1192	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -10.41	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00492% European (non-Finnish) · 58/1,179,054 alleles

Filtering AF 0.00386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.00398% 64/1,609,586 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00492%	20,329
Admixed American	0.00342%	29,261
Remaining individualsnot grpmax-eligible	0.00321%	31,156
African / African-American	0.00267%	37,400

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: DDHD2
Protein: p.Ser129Leu
Coding: c.386C>T
MANE Select: NM_015214
dbSNP: rs748398783
Type: single nucleotide variant
Location: chr8:38234559 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70

Full DDHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 54 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 54 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

DDHD2 p.Ser129= Uncertain significance ★ same residue
DDHD2 p.Ser129Ala Uncertain significance ★ ⚠ same residue
PLPP5 p.His129Tyr Uncertain significance ★ ⚠ same residue
DDHD2 c.1126-2A>G Likely pathogenic ★★ same condition
DDHD2 c.1248+2T>C Likely pathogenic ★★ same condition
DDHD2 p.Arg232Ter Pathogenic ★★ same condition
DDHD2 p.Arg329Ter Pathogenic ★★ same condition
DDHD2 p.Arg516Ter 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/ddhd2-p-ser129leu (accessed [today's date]).

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