Is MADD p.Pro157Ser (c.469C>T) pathogenic?

MADD p.Pro157Ser (c.469C>T) is classified Uncertain significance in MADD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-15). AlphaMissense: likely benign (0.1726); Ultra-rare (popmax 0.0756%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MADD p.Pro157Ser (c.469C>T)?

MADD p.Pro157Ser (c.469C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MADD p.Pro157Ser (c.469C>T) in the general population?

MADD p.Pro157Ser (c.469C>T) is ultra-rare (popmax 0.0756%, nfe) (gnomAD).

What do computational predictors say about MADD p.Pro157Ser (c.469C>T)?

AlphaMissense predicts likely benign (score 0.1726) — an in-silico prediction, not a clinical call.

MADD p.Pro157Ser

c.469C>T · rs187671926 · VCV2349368

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1726 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0756%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1726	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -5.46	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 7.7	GERP 2.5, phastCons 1
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0756% European (non-Finnish) · 892/1,180,026 alleles

Filtering AF 0.0714% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0698%

Overall 0.0633% 1,021/1,614,186 alleles · ultra-rare exomes 958/1,461,812 · genomes 63/152,374 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.103%	969
European (non-Finnish)grpmax	0.0756%	1,323
Remaining individualsnot grpmax-eligible	0.0656%	1,525
African / African-American	0.024%	4,171
Admixed American	0.005%	20,012
South Asian	0.0011%	91,088

Finnish 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.Pro157Ser
Coding: c.469C>T
MANE Select: NM_001376571
dbSNP: rs187671926
Type: single nucleotide variant
Location: chr11:47274969 (GRCh38)
Gene constraint: LOEUF 0.725 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.59
Residue 157: the udenn domain; the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MADD p.Ala1029Val Uncertain significance ★★ ⚠ same condition
MADD p.Arg1077Gly Uncertain significance ★★ ⚠ same condition
MADD p.Arg1273His Uncertain significance ★★ ⚠ same condition
MADD p.Arg170His Uncertain significance ★★ ⚠ same condition
MADD p.Arg699His Uncertain significance ★★ ⚠ same condition
MADD p.Arg754Cys Uncertain significance ★★ ⚠ same condition
MADD p.Arg855Gln Uncertain significance ★★ ⚠ same condition
MADD p.Asp752Gly 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-pro157ser (accessed [today's date]).

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