Is DIS3 p.Ser633Pro (c.1897T>C) pathogenic?

DIS3 p.Ser633Pro (c.1897T>C) is classified Uncertain significance in DIS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-06). AlphaMissense: likely pathogenic (0.9737); Very rare (popmax 0.00034%, nfe).

How common is DIS3 p.Ser633Pro (c.1897T>C) in the general population?

DIS3 p.Ser633Pro (c.1897T>C) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about DIS3 p.Ser633Pro (c.1897T>C)?

AlphaMissense predicts likely pathogenic (score 0.9737) — an in-silico prediction, not a clinical call.

DIS3 p.Ser633Pro

c.1897T>C · rs1442172275 · VCV2494607

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9737 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9737	likely pathogenic
REVEL	0.178	moderately benign-leaning
SaProt	LLR -11.36	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 2.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 18 kb · p 0.072 · regional, not allelic
Overall
CADD	25.9	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 0.00034% European (non-Finnish) · 4/1,178,146 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,610,248 alleles · very rare

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.Ser633Pro
Coding: c.1897T>C
MANE Select: NM_014953
dbSNP: rs1442172275
Type: single nucleotide variant
Location: chr13:72766045 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.12 · 3 PDB
Residue 633: the rnb domain

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-ser633pro (accessed [today's date]).

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