Is DIAPH1 p.Pro655Ala (c.1963C>G) pathogenic?

DIAPH1 p.Pro655Ala (c.1963C>G) is classified Uncertain significance in DIAPH1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.0678); Ultra-rare (popmax 0.0506%, afr); Associated with autosomal dominant nonsyndromic hearing loss 1.

How common is DIAPH1 p.Pro655Ala (c.1963C>G) in the general population?

DIAPH1 p.Pro655Ala (c.1963C>G) is ultra-rare (popmax 0.0506%, afr) (gnomAD).

What do computational predictors say about DIAPH1 p.Pro655Ala (c.1963C>G)?

AlphaMissense predicts likely benign (score 0.0678) — an in-silico prediction, not a clinical call.

DIAPH1 p.Pro655Ala

Q: What condition is associated with DIAPH1 p.Pro655Ala (c.1963C>G)?

DIAPH1 p.Pro655Ala (c.1963C>G) is associated with autosomal dominant nonsyndromic hearing loss 1, progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome (ClinVar).

c.1963C>G · rs201827139 · VCV844136

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0678 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0506%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant nonsyndromic hearing loss 1

Computational evidence

Protein change
AlphaMissense	0.0678	likely benign
REVEL	0.251	benign-leaning
SaProt	LLR -10.56	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 0.93, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 43 kb · p 0.09 · regional, not allelic
Overall
CADD	23.3	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 0.0506% African / African-American · 37/73,178 alleles

Filtering AF 0.0377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0332%

Overall 0.00265% 41/1,545,700 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0506%	1,978
Remaining individualsnot grpmax-eligible	0.00333%	29,990
Admixed American	0.00198%	50,590
European (non-Finnish)	8.74e-05%	1,144,778

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.Pro655Ala
Coding: c.1963C>G
MANE Select: NM_005219
dbSNP: rs201827139
Type: single nucleotide variant
Location: chr5:141573887 (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 655: 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 DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

Similar variants

DIAPH1 p.Pro655His Uncertain significance ★★ ⚠ same residue
DIAPH1 p.Pro655Arg Benign/Likely benign ★★ ⚠ 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

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-pro655ala (accessed [today's date]).

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