Is DMP1 p.Asn498Ser (c.1493A>G) pathogenic?

DMP1 p.Asn498Ser (c.1493A>G) is classified Uncertain significance in DMP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-21). AlphaMissense: ambiguous (0.3906); Rare (popmax 0.116%, afr); Associated with hypophosphatemic rickets, autosomal recessive, 1.

What condition is associated with DMP1 p.Asn498Ser (c.1493A>G)?

DMP1 p.Asn498Ser (c.1493A>G) is associated with hypophosphatemic rickets, autosomal recessive, 1 (ClinVar).

How common is DMP1 p.Asn498Ser (c.1493A>G) in the general population?

DMP1 p.Asn498Ser (c.1493A>G) is rare (popmax 0.116%, afr) (gnomAD).

How is Autosomal recessive hypophosphatemic rickets inherited?

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

What do computational predictors say about DMP1 p.Asn498Ser (c.1493A>G)?

AlphaMissense predicts ambiguous (score 0.3906) — an in-silico prediction, not a clinical call.

DMP1 p.Asn498Ser

c.1493A>G · rs373096835 · VCV2079270

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3906 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, afr)

Conditions

hypophosphatemic rickets, autosomal recessive, 1

Computational evidence

Protein change
AlphaMissense	0.3906	ambiguous
REVEL	0.324	indeterminate
SaProt	LLR -5.61	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Overall
CADD	22.4	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 0.116% African / African-American · 87/75,082 alleles

Filtering AF 0.0962% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0889%

Overall 0.007% 113/1,614,280 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.116%	863
Remaining individualsnot grpmax-eligible	0.0208%	4,809
Admixed American	0.015%	6,670
European (non-Finnish)	0.000339%	295,012

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: DMP1
Protein: p.Asn498Ser
Coding: c.1493A>G
MANE Select: NM_001142327 · reported on NM_004407
dbSNP: rs373096835
Type: single nucleotide variant
Location: chr4:87663271 (GRCh38)
Structure: AlphaFold pLDDT 53.56 · 1 PDB
Residue 498: the 'required for transcriptional activation' region; the 'interaction with ccnd1, ccnd2 and ccnd3' region

Full DMP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypophosphatemic rickets, autosomal recessive, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive hypophosphatemic rickets (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

DMP1 p.Gly135Ter Pathogenic/Likely pathogenic ★★ same condition
DMP1 p.Met1Val Pathogenic/Likely pathogenic ★★ same condition
DMP1 c.*159T>A Uncertain significance ★★ same condition
DMP1 c.*77T>C Uncertain significance ★★ same condition
DMP1 p.Arg173Trp Uncertain significance ★★ ⚠ same condition
DMP1 p.Arg302Ile Uncertain significance ★★ ⚠ same condition
DMP1 p.Asn233Lys Uncertain significance ★★ ⚠ same condition
DMP1 p.Asn332Lys 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/dmp1-p-asn498ser (accessed [today's date]).

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