Is DDHD2 p.Arg516Gln (c.1547G>A) pathogenic?

DDHD2 p.Arg516Gln (c.1547G>A) is classified Uncertain significance in DDHD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-02). AlphaMissense: likely pathogenic (0.9679); Very rare (popmax 0.00834%, amr); Associated with hereditary spastic paraplegia 54.

What condition is associated with DDHD2 p.Arg516Gln (c.1547G>A)?

DDHD2 p.Arg516Gln (c.1547G>A) is associated with hereditary spastic paraplegia 54 (ClinVar).

How common is DDHD2 p.Arg516Gln (c.1547G>A) in the general population?

DDHD2 p.Arg516Gln (c.1547G>A) is very rare (popmax 0.00834%, amr) (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.Arg516Gln (c.1547G>A)?

AlphaMissense predicts likely pathogenic (score 0.9679) — an in-silico prediction, not a clinical call.

DDHD2 p.Arg516Gln

c.1547G>A · rs1475417610 · VCV860257

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9679 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary spastic paraplegia 54

Computational evidence

Protein change
AlphaMissense	0.9679	likely pathogenic
REVEL	0.615	indeterminate
SaProt	LLR -12.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00834% Admixed American · 5/59,956 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.0013% 21/1,613,944 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,991
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	0.00119%	84,287

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.Arg516Gln
Coding: c.1547G>A
MANE Select: NM_015214
dbSNP: rs1475417610
Type: single nucleotide variant
Location: chr8:38252217 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 516: a UniProt-annotated variant site (in spg54; likely pathogenic; loss of triacylglycerol hydrolase activity); the ddhd 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.Arg516Ter Pathogenic ★★ 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.Asp660His Pathogenic/Likely pathogenic ★★ same condition
DDHD2 p.Gln286Ter Pathogenic/Likely pathogenic ★★ same condition
DDHD2 p.Trp115Ter 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-arg516gln (accessed [today's date]).

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