Is DIAPH1 p.Pro689= (c.2067A>C) pathogenic?

DIAPH1 p.Pro689= (c.2067A>C) is classified Likely benign in DIAPH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-22). Ultra-rare (popmax 0.03%, amr); Associated with autosomal dominant nonsyndromic hearing loss 1.

What condition is associated with DIAPH1 p.Pro689= (c.2067A>C)?

DIAPH1 p.Pro689= (c.2067A>C) is associated with autosomal dominant nonsyndromic hearing loss 1, progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (ClinVar).

How common is DIAPH1 p.Pro689= (c.2067A>C) in the general population?

DIAPH1 p.Pro689= (c.2067A>C) is ultra-rare (popmax 0.03%, amr) (gnomAD).

DIAPH1 p.Pro689=

c.2067A>C · rs876657451 · VCV227301

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Conditions

autosomal dominant nonsyndromic hearing loss 1

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 -0.29	GERP -2, phastCons 0.35
Overall
CADD	0.25	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.03% Admixed American · 6/19,998 alleles

Filtering AF 0.013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00892%

Overall 0.00774% 66/852,380 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,333
African / African-American	0.0232%	4,311
South Asian	0.0138%	7,239
Finnishnot grpmax-eligible	0.0119%	8,408
East Asian	0.00932%	10,732
European (non-Finnish)	0.00629%	15,905
Remaining individualsnot grpmax-eligible	0.00336%	29,798

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: DIAPH1
Protein: p.Pro689=
Coding: c.2067A>C
MANE Select: NM_005219
dbSNP: rs876657451
Type: single nucleotide variant
Location: chr5:141573783 (GRCh38)
Gene constraint: LOEUF 0.367 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.04 · 1 PDB
Residue 689: the fh1 domain; the 'disordered' region

Full DIAPH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant nonsyndromic hearing loss 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

Similar variants

DIAPH1 p.Pro689Arg Uncertain significance ★ ⚠ same residue
DIAPH1 c.145-1G>A Likely pathogenic ★★ same condition
DIAPH1 c.684+1G>A Pathogenic ★★ same condition
DIAPH1 p.Arg1049Ter Pathogenic ★★ same condition
DIAPH1 p.Arg1213Ter Pathogenic ★★ same condition
DIAPH1 p.Arg331Ter Pathogenic ★★ same condition
DIAPH1 p.Arg351Ter Pathogenic ★★ same condition
DIAPH1 p.Gln778Ter Pathogenic/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/diaph1-p-pro689 (accessed [today's date]).

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