Is MARVELD2 p.Arg481= (c.1443G>A) pathogenic?

MARVELD2 p.Arg481= (c.1443G>A) is classified Conflicting classifications of pathogenicity in MARVELD2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-08). Ultra-rare (popmax 0.0285%, sas); Associated with autosomal recessive nonsyndromic hearing loss 49.

What condition is associated with MARVELD2 p.Arg481= (c.1443G>A)?

MARVELD2 p.Arg481= (c.1443G>A) is associated with autosomal recessive nonsyndromic hearing loss 49 (ClinVar).

How common is MARVELD2 p.Arg481= (c.1443G>A) in the general population?

MARVELD2 p.Arg481= (c.1443G>A) is ultra-rare (popmax 0.0285%, sas) (gnomAD).

MARVELD2 p.Arg481=

c.1443G>A · rs753543276 · VCV354094

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0285%, sas)

Conditions

autosomal recessive nonsyndromic hearing loss 49

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 1.8, phastCons 1
Overall
CADD	12.32	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0285% South Asian · 26/91,094 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.0018% 29/1,614,074 alleles · ultra-rare exomes 27/1,461,880 · genomes 2/152,194 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0285%	3,504
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00133%	74,930

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: MARVELD2
Protein: p.Arg481=
Coding: c.1443G>A
MANE Select: NM_001038603
dbSNP: rs753543276
Type: single nucleotide variant
Location: chr5:69433033 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 66.90 · 3 PDB
Residue 481: the ocel domain; an α-helix

Full MARVELD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive nonsyndromic hearing loss 49 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MARVELD2 c.1183-1G>A Pathogenic/Likely pathogenic ★★ same condition
MARVELD2 c.1331+1G>A Pathogenic ★★ same condition
MARVELD2 c.1331+2T>C Pathogenic/Likely pathogenic ★★ same condition
MARVELD2 p.Arg164Ter Likely pathogenic ★★ same condition
MARVELD2 p.Arg455Ter Likely pathogenic ★★ same condition
MARVELD2 p.Arg500Ter Pathogenic/Likely pathogenic ★★ same condition
MARVELD2 p.Ser63Ter Likely pathogenic ★★ same condition
MARVELD2 p.Ala152Thr 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/marveld2-p-arg481 (accessed [today's date]).

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