Is DIAPH3 p.Arg448Pro (c.1343G>C) pathogenic?

DIAPH3 p.Arg448Pro (c.1343G>C) is classified Uncertain significance in DIAPH3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-18). AlphaMissense: likely pathogenic (0.9317); Ultra-rare (popmax 0.0942%, eas); Associated with auditory neuropathy.

What condition is associated with DIAPH3 p.Arg448Pro (c.1343G>C)?

DIAPH3 p.Arg448Pro (c.1343G>C) is associated with auditory neuropathy (ClinVar).

How common is DIAPH3 p.Arg448Pro (c.1343G>C) in the general population?

DIAPH3 p.Arg448Pro (c.1343G>C) is ultra-rare (popmax 0.0942%, eas) (gnomAD).

What do computational predictors say about DIAPH3 p.Arg448Pro (c.1343G>C)?

AlphaMissense predicts likely pathogenic (score 0.9317) — an in-silico prediction, not a clinical call.

DIAPH3 p.Arg448Pro

c.1343G>C · rs145827856 · VCV1219706

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9317 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0942%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

auditory neuropathy

Computational evidence

Protein change
AlphaMissense	0.9317	likely pathogenic · top 5% in DIAPH3
REVEL	0.791	moderately pathogenic-leaning
SaProt	LLR -9.96	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 497 kb · p 0.83 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0942% East Asian · 42/44,604 alleles

Filtering AF 0.0716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0636%

Overall 0.00749% 120/1,602,080 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0942%	1,062
South Asian	0.0804%	1,243
Remaining individualsnot grpmax-eligible	0.00806%	12,403

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: DIAPH3
Protein: p.Arg448Pro
Coding: c.1343G>C
MANE Select: NM_001042517
dbSNP: rs145827856
Type: single nucleotide variant
Location: chr13:59991176 (GRCh38)
Gene constraint: LOEUF 0.889 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.33 · 2 PDB
Residue 448: the gbd/fh3 domain

Full DIAPH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

auditory neuropathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DIAPH3 p.Arg448Gln Uncertain significance ★★ ⚠ same residue
DIAPH3 p.Arg448Ter Uncertain significance ★★ same residue
DIAPH3 p.Asp476Tyr Uncertain significance ★ ⚠ same condition
DIAPH3 p.Met790Ile Uncertain significance ★ ⚠ same condition
DIAPH3 p.Ala500Val Uncertain significance ★★ ⚠ same type
DIAPH3 p.Ala546Thr Uncertain significance ★★ ⚠ same type
DIAPH3 p.Arg1027His Uncertain significance ★★ ⚠ same type
DIAPH3 p.Arg1048Cys Uncertain significance ★★ ⚠ same type

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/diaph3-p-arg448pro (accessed [today's date]).

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