Is DIAPH1 p.Pro677Gln (c.2030C>A) pathogenic?

DIAPH1 p.Pro677Gln (c.2030C>A) is classified Conflicting classifications of pathogenicity in DIAPH1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.1137); Ultra-rare (popmax 0.0117%, nfe); Associated with Inborn genetic diseases.

How common is DIAPH1 p.Pro677Gln (c.2030C>A) in the general population?

DIAPH1 p.Pro677Gln (c.2030C>A) is ultra-rare (popmax 0.0117%, nfe) (gnomAD).

What do computational predictors say about DIAPH1 p.Pro677Gln (c.2030C>A)?

AlphaMissense predicts likely benign (score 0.1137) — an in-silico prediction, not a clinical call.

DIAPH1 p.Pro677Gln

Q: What condition is associated with DIAPH1 p.Pro677Gln (c.2030C>A)?

DIAPH1 p.Pro677Gln (c.2030C>A) is associated with Inborn genetic diseases, autosomal dominant nonsyndromic hearing loss 1, progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (ClinVar).

c.2030C>A · rs761912885 · VCV850652

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1137 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1137	likely benign
REVEL	0.436	indeterminate
SaProt	LLR -11.46	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 0.57	GERP 0.8, phastCons 0.001
Regional constraint	o/e 1.07	unconstrained · MANE · 43 kb · p 0.09 · regional, not allelic
Overall
CADD	19.66	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 0.0117% European (non-Finnish) · 132/1,127,524 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00946%

Overall 0.00942% 143/1,518,288 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0117%	8,542
Finnishnot grpmax-eligible	0.00682%	14,669
Admixed American	0.00604%	16,551
Remaining individualsnot grpmax-eligible	0.00339%	29,474
African / African-American	0.00138%	72,556
South Asian	0.0013%	76,680

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.Pro677Gln
Coding: c.2030C>A
MANE Select: NM_005219
dbSNP: rs761912885
Type: single nucleotide variant
Location: chr5:141573820 (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 677: the fh1 domain; the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant nonsyndromic hearing loss 1 progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

Similar variants

DIAPH1 p.Pro677Leu Uncertain significance ★★ ⚠ same residue
DIAPH1 p.Pro677Arg Uncertain significance ★ ⚠ same residue
DIAPH1 p.Pro677Ser 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

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-pro677gln (accessed [today's date]).

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