Is MADD p.Ala361= (c.1083A>G) pathogenic?

MADD p.Ala361= (c.1083A>G) is classified Benign in MADD (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-17). Low-frequency (popmax 1.64%, nfe); Associated with MADD-related disorder.

What condition is associated with MADD p.Ala361= (c.1083A>G)?

MADD p.Ala361= (c.1083A>G) is associated with MADD-related disorder (ClinVar).

How common is MADD p.Ala361= (c.1083A>G) in the general population?

MADD p.Ala361= (c.1083A>G) is low-frequency (popmax 1.64%, nfe) (gnomAD).

MADD p.Ala361=

c.1083A>G · rs34602269 · VCV3055675

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 1.64%, nfe)

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 -5	GERP -4.6
Overall
CADD	3.265	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.64% European (non-Finnish) · 19,377/1,180,014 alleles

Filtering AF 1.62% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.61%

Overall 1.45% 23,418/1,614,118 alleles · low-frequency exomes 21,719/1,461,810 · genomes 1,699/152,308 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	4.8%	21
European (non-Finnish)grpmax	1.64%	61
Remaining individualsnot grpmax-eligible	1.56%	64
Middle Eastern	1.3%	77
Admixed American	1.19%	84
South Asian	0.416%	240
Finnishnot grpmax-eligible	0.392%	255
African / African-American	0.249%	401
Amishnot grpmax-eligible	0.11%	912
East Asian	0.078%	1,283

Ashkenazi Jewish 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: MADD
Protein: p.Ala361=
Coding: c.1083A>G
MANE Select: NM_001376571
dbSNP: rs34602269
Type: single nucleotide variant
Location: chr11:47276851 (GRCh38)
Gene constraint: LOEUF 0.725 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.59
Residue 361: 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-ala361 (accessed [today's date]).

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