Is MADD p.Pro372Leu (c.1115C>T) pathogenic?

MADD p.Pro372Leu (c.1115C>T) is classified Uncertain significance in MADD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-29). AlphaMissense: likely pathogenic (0.9888); Very rare (popmax 0.000424%, nfe); Associated with deeah syndrome.

What condition is associated with MADD p.Pro372Leu (c.1115C>T)?

MADD p.Pro372Leu (c.1115C>T) is associated with deeah syndrome (ClinVar).

How common is MADD p.Pro372Leu (c.1115C>T) in the general population?

MADD p.Pro372Leu (c.1115C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about MADD p.Pro372Leu (c.1115C>T)?

AlphaMissense predicts likely pathogenic (score 0.9888) — an in-silico prediction, not a clinical call.

MADD p.Pro372Leu

Q: How is MADD-related developmental delay-endocrine dysfunction-hypohemoglobinemia syndrome inherited?

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

c.1115C>T · rs147713337 · VCV978040

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9888 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

deeah syndrome

Computational evidence

Protein change
AlphaMissense	0.9888	likely pathogenic
REVEL	0.612	indeterminate
SaProt	LLR -15.18	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,850 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,680 alleles · very rare

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.Pro372Leu
Coding: c.1115C>T
MANE Select: NM_000126 · reported on NM_001376571
dbSNP: rs147713337
Type: single nucleotide variant
Location: chr11:47278184 (GRCh38)
Structure: AlphaFold pLDDT 94.00 · 4 PDB

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

Disease context

deeah syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MADD-related developmental delay-endocrine dysfunction-hypohemoglobinemia syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

MADD c.2816+1G>A Pathogenic ★★ same condition
MADD p.Ala1029Val Uncertain significance ★★ ⚠ same condition
MADD p.Arg754Cys Uncertain significance ★★ ⚠ same condition
MADD p.Cys648Phe Uncertain significance ★★ ⚠ same condition
MADD p.Ile1159Met Uncertain significance ★★ ⚠ same condition
MADD p.Val1129Glu Uncertain significance ★★ ⚠ same condition
MADD p.Arg765Gln Benign ★★ same condition
MADD p.Asn444Asp Benign/Likely benign ★★ ⚠ 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-pro372leu (accessed [today's date]).

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