Is DNALI1 p.Arg220Trp (c.658C>T) pathogenic?

DNALI1 p.Arg220Trp (c.658C>T) is classified Uncertain significance in DNALI1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-27). AlphaMissense: likely pathogenic (0.5821); Very rare (popmax 0.00439%, sas).

How common is DNALI1 p.Arg220Trp (c.658C>T) in the general population?

DNALI1 p.Arg220Trp (c.658C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about DNALI1 p.Arg220Trp (c.658C>T)?

AlphaMissense predicts likely pathogenic (score 0.5821) — an in-silico prediction, not a clinical call.

DNALI1 p.Arg220Trp

c.658C>T · rs751524648 · VCV2489625

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5821 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5821	likely pathogenic
REVEL	0.412	indeterminate
SaProt	LLR -13.29	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 2	GERP 0.98, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 8,063 bp · p 0.3 · regional, not allelic
Overall
CADD	27.1	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 0.00439% South Asian · 4/91,064 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000684% 10/1,461,770 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,766
Admixed American	0.00167%	59,992
European (non-Finnish)	0.000424%	235,994

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: DNALI1
Protein: p.Arg220Trp
Coding: c.658C>T
MANE Select: NM_003462
dbSNP: rs751524648
Type: single nucleotide variant
Location: chr1:37562162 (GRCh38)
Gene constraint: LOEUF 1.202 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.32 · 1 PDB
Residue 220: the 'disordered' region

Full DNALI1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNALI1 p.Leu196= Benign ★★ same type
DNALI1 p.Lys231Gln Benign ★★ ⚠ same type
DNALI1 p.Glu190Ter Likely pathogenic ★ same type
DNALI1 c.-21G>A Uncertain significance ★ same type
DNALI1 c.-29G>T Uncertain significance ★ same type
DNALI1 c.-42A>T Uncertain significance ★ same type
DNALI1 p.Ala144Val Uncertain significance ★ ⚠ same type
DNALI1 p.Ala194Thr 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/dnali1-p-arg220trp (accessed [today's date]).

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