Is MADD p.Arg327Ter (c.979C>T) pathogenic?

MADD p.Arg327Ter (c.979C>T) is classified Pathogenic/Likely pathogenic in MADD (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-09-04). Very rare (popmax 0.00381%, nfe); Associated with MADD-related disorder.

What condition is associated with MADD p.Arg327Ter (c.979C>T)?

MADD p.Arg327Ter (c.979C>T) is associated with MADD-related disorder, neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (ClinVar).

How common is MADD p.Arg327Ter (c.979C>T) in the general population?

MADD p.Arg327Ter (c.979C>T) is very rare (popmax 0.00381%, nfe) (gnomAD).

MADD p.Arg327Ter

c.979C>T · rs147179561 · VCV418287

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Conditions

MADD-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.3, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00381% European (non-Finnish) · 45/1,180,020 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00291% 47/1,613,974 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00381%	26,223
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Arg327Ter
Coding: c.979C>T
MANE Select: NM_000126 · reported on NM_001376571
dbSNP: rs147179561
Type: single nucleotide variant
Location: chr11:47276747 (GRCh38)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 327: the 'domain ii' region; an α-helix

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

Disease context

MADD-related disorder

Also linked: neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia

Similar variants

ETFA p.Thr327Asn Uncertain significance ★ ⚠ same residue
ETFA p.Thr327= Likely benign ★ same residue
ETFA p.Arg122Lys Likely pathogenic ★★ same condition
ETFA p.Arg18Ter Pathogenic/Likely pathogenic ★★ same condition
ETFA p.Arg209Ter Pathogenic/Likely pathogenic ★★ same condition
ETFA p.Arg223Ter Pathogenic/Likely pathogenic ★★ same condition
ETFA p.Gln65Ter Likely pathogenic ★★ same condition
ETFA p.Gly116Arg Likely pathogenic ★★ 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-arg327ter (accessed [today's date]).

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