Is DHPS p.Arg154fs (c.460_461del) pathogenic?

DHPS p.Arg154fs (c.460461del) is classified Conflicting classifications of pathogenicity in DHPS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-30). Ultra-rare (popmax 0.0165%, sas); Associated with neurodevelopmental disorder with seizures and speech and walking impairment.

What condition is associated with DHPS p.Arg154fs (c.460_461del)?

DHPS p.Arg154fs (c.460_461del) is associated with neurodevelopmental disorder with seizures and speech and walking impairment (ClinVar).

How common is DHPS p.Arg154fs (c.460_461del) in the general population?

DHPS p.Arg154fs (c.460_461del) is ultra-rare (popmax 0.0165%, sas) (gnomAD).

DHPS p.Arg154fs

c.460_461del · rs541400419 · VCV1702982

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, sas)

Conditions

neurodevelopmental disorder with seizures and speech and walking impairment

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.072	GERP -2.7, phastCons 0.003
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% South Asian · 15/91,082 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00824% 133/1,614,066 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0165%	6,072
Middle Eastern	0.0164%	6,084
European (non-Finnish)	0.00839%	11,920
African / African-American	0.00801%	12,486
Remaining individualsnot grpmax-eligible	0.008%	12,498
Finnishnot grpmax-eligible	0.00468%	21,346
East Asian	0.00445%	22,449
Admixed American	0.00333%	29,997

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: DHPS
Protein: p.Arg154fs
Coding: c.460_461del
MANE Select: NM_001930
dbSNP: rs541400419
Type: Deletion
Location: chr19:12679834 (GRCh38)
Gene constraint: LOEUF 0.824 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.95 · 89 PDB

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

Disease context

neurodevelopmental disorder with seizures and speech and walking impairment — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DHPS p.Tyr305_Ile306del Likely pathogenic ★★ same condition
DHPS p.Arg154Thr Uncertain significance ★ ⚠ same residue
DHPS c.1014+1G>A Conflicting classifications of pathogenicity ★ same condition
DHPS p.Asn173Ser Conflicting classifications of pathogenicity ★ ⚠ 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/dhps-p-arg154fs (accessed [today's date]).

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