Is DHPS p.Asn173Ser (c.518A>G) pathogenic?

DHPS p.Asn173Ser (c.518A>G) is classified Conflicting classifications of pathogenicity in DHPS (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-04-22). AlphaMissense: likely benign (0.3013); Ultra-rare (popmax 0.0114%, nfe); Associated with DHPS-related disorder.

What condition is associated with DHPS p.Asn173Ser (c.518A>G)?

DHPS p.Asn173Ser (c.518A>G) is associated with DHPS-related disorder, neurodevelopmental disorder with seizures and speech and walking impairment (ClinVar).

How common is DHPS p.Asn173Ser (c.518A>G) in the general population?

DHPS p.Asn173Ser (c.518A>G) is ultra-rare (popmax 0.0114%, nfe) (gnomAD).

What do computational predictors say about DHPS p.Asn173Ser (c.518A>G)?

AlphaMissense predicts likely benign (score 0.3013) — an in-silico prediction, not a clinical call.

DHPS p.Asn173Ser

c.518A>G · rs758100382 · VCV560194

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.3013 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0114%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

DHPS-related disorder

Computational evidence

Protein change
AlphaMissense	0.3013	likely benign
REVEL	0.347	indeterminate
SaProt	LLR -11.76	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 5,925 bp · p 0.58 · regional, not allelic
Overall
CADD	25.9	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 0.0114% European (non-Finnish) · 134/1,180,040 alleles

Filtering AF 0.00977% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00912%

Overall 0.00948% 153/1,614,054 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0114%	8,806
Remaining individualsnot grpmax-eligible	0.008%	12,497
Admixed American	0.00667%	14,999
South Asian	0.00549%	18,218
Finnishnot grpmax-eligible	0.00312%	32,021
African / African-American	0.00267%	37,461
East Asian	0.00223%	44,882

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.Asn173Ser
Coding: c.518A>G
MANE Select: NM_001930
dbSNP: rs758100382
Type: single nucleotide variant
Location: chr19:12679696 (GRCh38)
Gene constraint: LOEUF 0.824 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.95 · 89 PDB
Residue 173: a UniProt-annotated variant site (in nedsswi; decreased deoxyhypusine synthase activity); an α-helix

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

Disease context

DHPS-related disorder

Also linked: neurodevelopmental disorder with seizures and speech and walking impairment

Similar variants

DHPS c.1014+1G>A Conflicting classifications of pathogenicity ★ same condition
DHPS c.207+462G>A Benign same condition
DHPS p.Ala68= Benign same condition
DHPS p.Arg7= Likely benign same condition
DHPS p.Pro145= Likely benign same condition
DHPS p.Ser204= Benign same condition
DHPS p.Ser219= Benign same condition
DHPS p.Tyr305_Ile306del 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/dhps-p-asn173ser (accessed [today's date]).

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