Is DIS3 p.Arg611Cys (c.1831C>T) pathogenic?

DIS3 p.Arg611Cys (c.1831C>T) is classified Uncertain significance in DIS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-07). AlphaMissense: likely benign (0.2603); Ultra-rare (popmax 0.0134%, amr).

How common is DIS3 p.Arg611Cys (c.1831C>T) in the general population?

DIS3 p.Arg611Cys (c.1831C>T) is ultra-rare (popmax 0.0134%, amr) (gnomAD).

What do computational predictors say about DIS3 p.Arg611Cys (c.1831C>T)?

AlphaMissense predicts likely benign (score 0.2603) — an in-silico prediction, not a clinical call.

DIS3 p.Arg611Cys

c.1831C>T · VCV3502104

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2603 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2603	likely benign
REVEL	0.625	indeterminate
SaProt	LLR -11.98	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 9.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 18 kb · p 0.072 · 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 0.0134% Admixed American · 8/59,844 alleles

Filtering AF 0.00663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00448% 72/1,608,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0134%	7,480
South Asian	0.00551%	18,140
European (non-Finnish)	0.00476%	20,994
African / African-American	0.00267%	37,402
Finnishnot grpmax-eligible	0.00157%	63,884

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: DIS3
Protein: p.Arg611Cys
Coding: c.1831C>T
MANE Select: NM_014953
Type: single nucleotide variant
Location: chr13:72768837 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.12 · 3 PDB
Residue 611: the rnb domain; an α-helix

Full DIS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DIS3 p.Ala518Thr Uncertain significance ★★ ⚠ same type
DIS3 p.Ala401Val Benign ★★ ⚠ same type
DIS3 p.Ter959Gln Likely benign ★★ same type
PIBF1 p.Ile51Val Benign/Likely benign ★★ same type
PIBF1 p.Met73Thr Benign/Likely benign ★★ same type
DIS3 p.Arg638Ter Likely pathogenic ★ same type
DIS3 c.228+3G>A Uncertain significance ★ same type
DIS3 c.2511+1G>C 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/dis3-p-arg611cys (accessed [today's date]).

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