Is DMP1 p.Thr42Pro (c.124A>C) pathogenic?

DMP1 p.Thr42Pro (c.124A>C) is classified Conflicting classifications of pathogenicity in DMP1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-15). AlphaMissense: likely benign (0.0735); Ultra-rare (popmax 0.0869%, eas); Associated with hypophosphatemic rickets, autosomal recessive, 1.

What condition is associated with DMP1 p.Thr42Pro (c.124A>C)?

DMP1 p.Thr42Pro (c.124A>C) is associated with hypophosphatemic rickets, autosomal recessive, 1 (ClinVar).

How common is DMP1 p.Thr42Pro (c.124A>C) in the general population?

DMP1 p.Thr42Pro (c.124A>C) is ultra-rare (popmax 0.0869%, eas) (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.Thr42Pro (c.124A>C)?

AlphaMissense predicts likely benign (score 0.0735) — an in-silico prediction, not a clinical call.

DMP1 p.Thr42Pro

c.124A>C · rs369550864 · VCV2048257

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0735 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0869%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypophosphatemic rickets, autosomal recessive, 1

Computational evidence

Protein change
AlphaMissense	0.0735	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -5.00	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 -0.56	GERP -4
Overall
CADD	3.756	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 0.0869% East Asian · 39/44,860 alleles

Filtering AF 0.0653% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.0106% 171/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0976%	1,025
East Asiangrpmax	0.0869%	1,150
South Asian	0.0681%	1,469
Admixed American	0.00167%	60,026
European (non-Finnish)	0.000678%	147,500

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: DMP1
Protein: p.Thr42Pro
Coding: c.124A>C
MANE Select: NM_001142327 · reported on NM_004407
dbSNP: rs369550864
Type: single nucleotide variant
Location: chr4:87659241 (GRCh38)
Structure: AlphaFold pLDDT 53.56 · 1 PDB
Residue 42: the 'interaction with ccnd2' 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-thr42pro (accessed [today's date]).

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