Is DDHD2 p.Ser377Leu (c.1130C>T) pathogenic?

DDHD2 p.Ser377Leu (c.1130C>T) is classified Conflicting classifications of pathogenicity in DDHD2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0617); Ultra-rare (popmax 0.0734%, amr); Associated with hereditary spastic paraplegia.

What condition is associated with DDHD2 p.Ser377Leu (c.1130C>T)?

DDHD2 p.Ser377Leu (c.1130C>T) is associated with hereditary spastic paraplegia, hereditary spastic paraplegia 54 (ClinVar).

How common is DDHD2 p.Ser377Leu (c.1130C>T) in the general population?

DDHD2 p.Ser377Leu (c.1130C>T) is ultra-rare (popmax 0.0734%, amr) (gnomAD).

What do computational predictors say about DDHD2 p.Ser377Leu (c.1130C>T)?

AlphaMissense predicts likely benign (score 0.0617) — an in-silico prediction, not a clinical call.

DDHD2 p.Ser377Leu

c.1130C>T · rs145943165 · VCV645719

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0617 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0734%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0617	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.86	GERP -2.1
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	13.35	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 0.0734% Admixed American · 30/40,846 alleles

Filtering AF 0.0529% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0458%

Overall 0.0308% 458/1,486,516 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0734%	1,362
Ashkenazi Jewishnot grpmax-eligible	0.0389%	2,573
European (non-Finnish)	0.0347%	2,883
Remaining individualsnot grpmax-eligible	0.0299%	3,345
East Asian	0.0122%	8,169
Finnishnot grpmax-eligible	0.0114%	8,796
South Asian	0.00401%	24,925
African / African-American	0.00144%	69,404

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.Ser377Leu
Coding: c.1130C>T
MANE Select: NM_015214
dbSNP: rs145943165
Type: single nucleotide variant
Location: chr8:38247717 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 377: a UniProt-annotated variant site (in spg54; likely pathogenic; loss of triacylglycerol hydrolase activity)

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

Disease context

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

Also linked: hereditary spastic paraplegia 54

Similar variants

DDHD2 p.Ser377= Likely benign ★ 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-ser377leu (accessed [today's date]).

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