Is DDHD2 p.Arg242His (c.725G>A) pathogenic?

DDHD2 p.Arg242His (c.725G>A) is classified Conflicting classifications of pathogenicity in DDHD2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-08-26). AlphaMissense: likely pathogenic (0.9017); Very rare (popmax 0.004%, amr); Associated with Inborn genetic diseases.

What condition is associated with DDHD2 p.Arg242His (c.725G>A)?

DDHD2 p.Arg242His (c.725G>A) is associated with Inborn genetic diseases, hereditary spastic paraplegia 54 (ClinVar).

How common is DDHD2 p.Arg242His (c.725G>A) in the general population?

DDHD2 p.Arg242His (c.725G>A) is very rare (popmax 0.004%, amr) (gnomAD).

What do computational predictors say about DDHD2 p.Arg242His (c.725G>A)?

AlphaMissense predicts likely pathogenic (score 0.9017) — an in-silico prediction, not a clinical call.

DDHD2 p.Arg242His

c.725G>A · rs767497993 · VCV540290

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9017 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9017	likely pathogenic
REVEL	0.505	indeterminate
SaProt	LLR -13.76	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.45	acceptor gain · deltas
Pangolin	Δ0.42	gain · loss 0.31 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 0.91, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	34.0	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 0.004% Admixed American · 2/49,968 alleles

Filtering AF 0.00268% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00238%

Overall 0.00303% 48/1,585,198 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00488%	20,478
Admixed Americangrpmax	0.004%	24,984
European (non-Finnish)	0.00359%	27,893
African / African-American	0.00137%	72,906

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg242His
Coding: c.725G>A
MANE Select: NM_015214
dbSNP: rs767497993
Type: single nucleotide variant
Location: chr8:38242262 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 54

Similar variants

DDHD2 p.Arg242Cys 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-arg242his (accessed [today's date]).

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