Is DIXDC1 p.Ser231Arg (c.691A>C) pathogenic?

DIXDC1 p.Ser231Arg (c.691A>C) is classified Uncertain significance in DIXDC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-20). AlphaMissense: ambiguous (0.5366); Ultra-rare (popmax 0.0977%, sas).

How common is DIXDC1 p.Ser231Arg (c.691A>C) in the general population?

DIXDC1 p.Ser231Arg (c.691A>C) is ultra-rare (popmax 0.0977%, sas) (gnomAD).

What do computational predictors say about DIXDC1 p.Ser231Arg (c.691A>C)?

AlphaMissense predicts ambiguous (score 0.5366) — an in-silico prediction, not a clinical call.

DIXDC1 p.Ser231Arg

c.691A>C · rs781863884 · VCV3082631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5366 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0977%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5366	ambiguous
REVEL	0.244	benign-leaning
SaProt	LLR -6.57	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 50 kb · p 0.0089 · regional, not allelic
Overall
CADD	21.8	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 0.0977% South Asian · 89/91,082 alleles

Filtering AF 0.0812% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0752%

Overall 0.00564% 91/1,613,902 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0977%	1,023
Remaining individualsnot grpmax-eligible	0.0032%	31,233

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.Ser231Arg
Coding: c.691A>C
MANE Select: NM_001037954
dbSNP: rs781863884
Type: single nucleotide variant
Location: chr11:111980771 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.52 · 1 PDB
Residue 231: a modified residue (phosphoserine); the 'actin-binding' region; the 'disordered' region

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.Ala25Pro 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

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-ser231arg (accessed [today's date]).

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