Is DIAPH1 p.Pro618= (c.1854A>T) pathogenic?

DIAPH1 p.Pro618= (c.1854A>T) is classified Likely benign in DIAPH1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-03-01). Very rare (popmax 0.00629%, amr); Associated with progressive microcephaly-seizures-cortical blindness-developmental delay syndrome.

How common is DIAPH1 p.Pro618= (c.1854A>T) in the general population?

DIAPH1 p.Pro618= (c.1854A>T) is very rare (popmax 0.00629%, amr) (gnomAD).

DIAPH1 p.Pro618=

Q: What condition is associated with DIAPH1 p.Pro618= (c.1854A>T)?

DIAPH1 p.Pro618= (c.1854A>T) is associated with progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, autosomal dominant nonsyndromic hearing loss 1 (ClinVar).

c.1854A>T · rs374236039 · VCV667104

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00629%, amr)

Conditions

progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

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 -3.5	GERP -2.6
Overall
CADD	0.937	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00629% Admixed American · 3/47,726 alleles

Filtering AF 0.00167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000862%

Overall 0.00106% 16/1,511,806 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00629%	15,909
South Asian	0.00367%	27,213
Remaining individualsnot grpmax-eligible	0.00338%	29,565
African / African-American	0.00311%	32,164
Finnishnot grpmax-eligible	0.00181%	55,282
European (non-Finnish)	0.000442%	226,141

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.Pro618=
Coding: c.1854A>T
MANE Select: NM_005219
dbSNP: rs374236039
Type: single nucleotide variant
Location: chr5:141573996 (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 618: the fh1 domain; the 'disordered' region

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

Disease context

progressive microcephaly-seizures-cortical blindness-developmental delay syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant nonsyndromic hearing loss 1

Similar variants

DIAPH1 p.Pro618Leu Uncertain significance ★★ ⚠ same residue
DIAPH1 p.Pro618Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
DIAPH1 p.Pro618Thr Uncertain significance ★ ⚠ same residue
DIAPH1 p.Pro618_Pro620del Conflicting classifications of pathogenicity ★ same residue
DIAPH1 p.Pro618_Pro620dup Conflicting classifications of pathogenicity ★ same residue
DIAPH1 p.Pro618_Pro622del Uncertain significance ★ same residue
DIAPH1 c.145-1G>A Likely pathogenic ★★ same condition
DIAPH1 c.684+1G>A 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-pro618 (accessed [today's date]).

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