Is MARVELD2 p.Pro440= (c.1320C>A) pathogenic?

MARVELD2 p.Pro440= (c.1320C>A) is classified Conflicting classifications of pathogenicity in MARVELD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-09-27). Very rare (popmax 0.00831%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 49.

What condition is associated with MARVELD2 p.Pro440= (c.1320C>A)?

MARVELD2 p.Pro440= (c.1320C>A) is associated with autosomal recessive nonsyndromic hearing loss 49 (ClinVar).

How common is MARVELD2 p.Pro440= (c.1320C>A) in the general population?

MARVELD2 p.Pro440= (c.1320C>A) is very rare (popmax 0.00831%, nfe) (gnomAD).

MARVELD2 p.Pro440=

c.1320C>A · rs376627126 · VCV354093

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00831%, nfe)

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 -5.9	GERP -5.6
Overall
CADD	0.522	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00831% European (non-Finnish) · 98/1,179,990 alleles

Filtering AF 0.00697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00632% 102/1,613,914 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00831%	12,041
Remaining individualsnot grpmax-eligible	0.0048%	20,826
Admixed American	0.00167%	59,978

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.Pro440=
Coding: c.1320C>A
MANE Select: NM_001038603
dbSNP: rs376627126
Type: single nucleotide variant
Location: chr5:69432664 (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 440: the ocel domain

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-pro440 (accessed [today's date]).

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