Is DDHD1 p.Lys331Gln (c.991A>C) pathogenic?

DDHD1 p.Lys331Gln (c.991A>C) is classified Uncertain significance in DDHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-09). AlphaMissense: likely benign (0.1121); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 28.

What condition is associated with DDHD1 p.Lys331Gln (c.991A>C)?

DDHD1 p.Lys331Gln (c.991A>C) is associated with hereditary spastic paraplegia 28 (ClinVar).

How common is DDHD1 p.Lys331Gln (c.991A>C) in the general population?

DDHD1 p.Lys331Gln (c.991A>C) is absent from gnomAD v4.1 (gnomAD).

How is Autosomal recessive spastic paraplegia type 28 inherited?

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

What do computational predictors say about DDHD1 p.Lys331Gln (c.991A>C)?

AlphaMissense predicts likely benign (score 0.1121) — an in-silico prediction, not a clinical call.

DDHD1 p.Lys331Gln

c.991A>C · rs2503298344 · VCV2107802

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1121 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 28

Computational evidence

Protein change
AlphaMissense	0.1121	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -6.75	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 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 106 kb · p 7.8e-05 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DDHD1
Protein: p.Lys331Gln
Coding: c.991A>C
MANE Select: NM_001160148
dbSNP: rs2503298344
Type: single nucleotide variant
Location: chr14:53103704 (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-lys331gln (accessed [today's date]).

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