Is DIXDC1 p.Arg199Gln (c.596G>A) pathogenic?

DIXDC1 p.Arg199Gln (c.596G>A) is classified Uncertain significance in DIXDC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-01). AlphaMissense: ambiguous (0.4063); Very rare (popmax 0.00223%, eas).

How common is DIXDC1 p.Arg199Gln (c.596G>A) in the general population?

DIXDC1 p.Arg199Gln (c.596G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DIXDC1 p.Arg199Gln (c.596G>A)?

AlphaMissense predicts ambiguous (score 0.4063) — an in-silico prediction, not a clinical call.

DIXDC1 p.Arg199Gln

c.596G>A · VCV3502197

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4063 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Computational evidence

Protein change
AlphaMissense	0.4063	ambiguous
REVEL	0.452	indeterminate
SaProt	LLR -8.10	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 50 kb · p 0.0089 · regional, not allelic
Overall
CADD	33.0	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 0.00223% East Asian · 1/44,892 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000868% 14/1,613,490 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,892
Remaining individualsnot grpmax-eligible	0.0016%	62,456
European (non-Finnish)	0.00102%	98,318

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.Arg199Gln
Coding: c.596G>A
MANE Select: NM_001037954
Type: single nucleotide variant
Location: chr11:111974923 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.52 · 1 PDB
Residue 199: the 'actin-binding' region

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

Similar variants

DIXDC1 p.Arg199Trp Uncertain significance ★ ⚠ same residue
DIXDC1 p.Asn19Asp Benign ★★ same type
DIXDC1 p.Asp608= Benign ★★ same type
DIXDC1 p.Ala156Pro Uncertain significance ★ ⚠ same type
DIXDC1 p.Ala25Pro Uncertain significance ★ ⚠ same type
DIXDC1 p.Ala39Val Uncertain significance ★ ⚠ same type
DIXDC1 p.Arg138Gln 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-arg199gln (accessed [today's date]).

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