Is DIXDC1 p.Ala25Pro (c.73G>C) pathogenic?

DIXDC1 p.Ala25Pro (c.73G>C) is classified Uncertain significance in DIXDC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-09). AlphaMissense: likely pathogenic (0.9111); Ultra-rare (popmax 0.0175%, mid).

How common is DIXDC1 p.Ala25Pro (c.73G>C) in the general population?

DIXDC1 p.Ala25Pro (c.73G>C) is ultra-rare (popmax 0.0175%, mid) (gnomAD).

What do computational predictors say about DIXDC1 p.Ala25Pro (c.73G>C)?

AlphaMissense predicts likely pathogenic (score 0.9111) — an in-silico prediction, not a clinical call.

DIXDC1 p.Ala25Pro

c.73G>C · VCV3272179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9111 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9111	likely pathogenic · top 9% in DIXDC1
REVEL	0.465	indeterminate
SaProt	LLR -12.48	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 2.3, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 31 kb · p 0.21 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0175% Middle Eastern · 1/5,718 alleles

Filtering AF 0.00521% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00476%

Overall 0.00505% 81/1,604,168 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0175%	5,718
European (non-Finnish)	0.00638%	15,667
Remaining individualsnot grpmax-eligible	0.00483%	20,717
African / African-American	0.00134%	74,882
South Asian	0.00112%	89,530

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: DIXDC1
Protein: p.Ala25Pro
Coding: c.73G>C
MANE Select: NM_001037954
Type: single nucleotide variant
Location: chr11:111964561 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.52 · 1 PDB
Residue 25: the calponin-homology (ch) domain

Full DIXDC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DIXDC1 p.Asn19Asp Benign ★★ same type
DIXDC1 p.Asp608= Benign ★★ same type
DIXDC1 p.Ala156Pro Uncertain significance ★ ⚠ same type
DIXDC1 p.Ala39Val Uncertain significance ★ ⚠ same type
DIXDC1 p.Arg138Gln Uncertain significance ★ ⚠ same type
DIXDC1 p.Arg199Gln Uncertain significance ★ same type
DIXDC1 p.Arg199Trp Uncertain significance ★ ⚠ same type
DIXDC1 p.Arg268Trp Uncertain significance ★ ⚠ same type

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/dixdc1-p-ala25pro (accessed [today's date]).

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