Is DDHD2 p.Leu93Phe (c.279G>T) pathogenic?

DDHD2 p.Leu93Phe (c.279G>T) is classified Uncertain significance in DDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-24). AlphaMissense: ambiguous (0.5031); Very rare (popmax 0.00401%, afr); Associated with hereditary spastic paraplegia 54.

What condition is associated with DDHD2 p.Leu93Phe (c.279G>T)?

DDHD2 p.Leu93Phe (c.279G>T) is associated with hereditary spastic paraplegia 54 (ClinVar).

How common is DDHD2 p.Leu93Phe (c.279G>T) in the general population?

DDHD2 p.Leu93Phe (c.279G>T) is very rare (popmax 0.00401%, afr) (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.Leu93Phe (c.279G>T)?

AlphaMissense predicts ambiguous (score 0.5031) — an in-silico prediction, not a clinical call.

DDHD2 p.Leu93Phe

c.279G>T · rs1003263082 · VCV1503106

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5031 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary spastic paraplegia 54

Computational evidence

Protein change
AlphaMissense	0.5031	ambiguous
REVEL	0.261	benign-leaning
SaProt	LLR -8.20	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.46 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.077	GERP -4.5, phastCons 0.49
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	21.2	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 0.00401% African / African-American · 3/74,806 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000806% 13/1,611,942 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,935
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,582
Remaining individualsnot grpmax-eligible	0.00321%	31,186
European (non-Finnish)	0.000593%	168,524

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.Leu93Phe
Coding: c.279G>T
MANE Select: NM_015214
dbSNP: rs1003263082
Type: single nucleotide variant
Location: chr8:38234452 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 93: the wwe domain

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.Leu93= Conflicting classifications of pathogenicity ★ 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
DDHD2 p.Asp660His Pathogenic/Likely pathogenic ★★ same condition
DDHD2 p.Gln286Ter Pathogenic/Likely 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-leu93phe (accessed [today's date]).

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