Is DIAPH1 p.Pro717Ser (c.2149C>T) pathogenic?

DIAPH1 p.Pro717Ser (c.2149C>T) is classified Uncertain significance in DIAPH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-03). AlphaMissense: likely benign (0.1622); Very rare (popmax 0.00171%, amr); Associated with autosomal dominant nonsyndromic hearing loss 1.

What condition is associated with DIAPH1 p.Pro717Ser (c.2149C>T)?

DIAPH1 p.Pro717Ser (c.2149C>T) is associated with autosomal dominant nonsyndromic hearing loss 1, progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (ClinVar).

How common is DIAPH1 p.Pro717Ser (c.2149C>T) in the general population?

DIAPH1 p.Pro717Ser (c.2149C>T) is very rare (popmax 0.00171%, amr) (gnomAD).

What do computational predictors say about DIAPH1 p.Pro717Ser (c.2149C>T)?

AlphaMissense predicts likely benign (score 0.1622) — an in-silico prediction, not a clinical call.

DIAPH1 p.Pro717Ser

c.2149C>T · rs2099895535 · VCV950834

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1622 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00171%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal dominant nonsyndromic hearing loss 1

Computational evidence

Protein change
AlphaMissense	0.1622	likely benign
REVEL	0.347	indeterminate
SaProt	LLR -11.15	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.8	GERP 2.2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 43 kb · p 0.09 · regional, not allelic
Overall
CADD	21.9	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 0.00171% Admixed American · 1/58,450 alleles

Overall 0.000138% 2/1,448,476 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00171%	58,450
South Asian	0.00111%	90,276

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.Pro717Ser
Coding: c.2149C>T
MANE Select: NM_005219
dbSNP: rs2099895535
Type: single nucleotide variant
Location: chr5:141573701 (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 717: 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 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
DIAPH1 c.402+5G>A 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/diaph1-p-pro717ser (accessed [today's date]).

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