Is DMP1 p.Pro419Ser (c.1255C>T) pathogenic?

DMP1 p.Pro419Ser (c.1255C>T) is classified Conflicting classifications of pathogenicity in DMP1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-06-12). AlphaMissense: likely benign (0.0783); Ultra-rare (popmax 0.0561%, nfe); Associated with hypophosphatemic rickets, autosomal recessive, 1.

What condition is associated with DMP1 p.Pro419Ser (c.1255C>T)?

DMP1 p.Pro419Ser (c.1255C>T) is associated with hypophosphatemic rickets, autosomal recessive, 1 (ClinVar).

How common is DMP1 p.Pro419Ser (c.1255C>T) in the general population?

DMP1 p.Pro419Ser (c.1255C>T) is ultra-rare (popmax 0.0561%, nfe) (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.Pro419Ser (c.1255C>T)?

AlphaMissense predicts likely benign (score 0.0783) — an in-silico prediction, not a clinical call.

DMP1 p.Pro419Ser

c.1255C>T · rs140275311 · VCV907170

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0783 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0561%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypophosphatemic rickets, autosomal recessive, 1

Computational evidence

Protein change
AlphaMissense	0.0783	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -3.50	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 0.36	GERP -2, phastCons 0.025
Overall
CADD	1.331	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 0.0561% European (non-Finnish) · 662/1,180,016 alleles

Filtering AF 0.0525% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0511%

Overall 0.0439% 709/1,614,168 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0561%	1,783
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0368%	2,718
Admixed American	0.025%	4,002
African / African-American	0.008%	12,507

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.Pro419Ser
Coding: c.1255C>T
MANE Select: NM_004407
dbSNP: rs140275311
Type: single nucleotide variant
Location: chr4:87663033 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 47.80
Residue 419: the 'disordered' 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.Pro419Leu Uncertain significance ★ ⚠ same residue
DMP1 p.Pro419= Likely benign ★ same residue
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

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-pro419ser (accessed [today's date]).

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