Is MADD p.Pro419= (c.1257A>G) pathogenic?

MADD p.Pro419= (c.1257A>G) is classified Likely benign in MADD (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-17). Rare (popmax 0.333%, afr); Associated with MADD-related disorder.

What condition is associated with MADD p.Pro419= (c.1257A>G)?

MADD p.Pro419= (c.1257A>G) is associated with MADD-related disorder (ClinVar).

How common is MADD p.Pro419= (c.1257A>G) in the general population?

MADD p.Pro419= (c.1257A>G) is rare (popmax 0.333%, afr) (gnomAD).

MADD p.Pro419=

c.1257A>G · rs112202533 · VCV3034323

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.333%, afr)

Conditions

MADD-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -4
Overall
CADD	5.607	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.333% African / African-American · 250/75,056 alleles

Filtering AF 0.299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.286%

Overall 0.0186% 301/1,614,116 alleles · rare exomes 163/1,461,778 · genomes 138/152,338 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.333%	300
Admixed American	0.045%	2,223
Remaining individualsnot grpmax-eligible	0.0336%	2,976
European (non-Finnish)	0.000254%	393,321

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: MADD
Protein: p.Pro419=
Coding: c.1257A>G
MANE Select: NM_001376571
dbSNP: rs112202533
Type: single nucleotide variant
Location: chr11:47279046 (GRCh38)
Gene constraint: LOEUF 0.725 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.59
Residue 419: the cdenn domain; a UniProt-annotated variant site (in deeah; uncertain significance); a UniProt-annotated variant site (in deeah and neddish; uncertain significance)

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

Disease context

MADD-related disorder

Similar variants

MADD p.Arg327Ter Pathogenic/Likely pathogenic ★★ same condition
MADD p.Cys648Phe Uncertain significance ★★ ⚠ same condition
MADD p.Arg190Ter Likely pathogenic ★ same condition
MADD c.2817-79G>A Uncertain significance ★ same condition
MADD p.Ser128Pro Uncertain significance ★ ⚠ same condition
MADD p.Ser829Asn Uncertain significance ★ ⚠ same condition
MADD p.Arg1094Trp Uncertain significance ⚠ same condition
MADD p.Arg534Trp 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/madd-p-pro419 (accessed [today's date]).

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