Is DIS3L p.Pro712Ser (c.2134C>T) pathogenic?

DIS3L p.Pro712Ser (c.2134C>T) is classified Uncertain significance in DIS3L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: likely pathogenic (0.6678); Very rare (popmax 0.00167%, amr).

How common is DIS3L p.Pro712Ser (c.2134C>T) in the general population?

DIS3L p.Pro712Ser (c.2134C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about DIS3L p.Pro712Ser (c.2134C>T)?

AlphaMissense predicts likely pathogenic (score 0.6678) — an in-silico prediction, not a clinical call.

DIS3L p.Pro712Ser

c.2134C>T · VCV4011845

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6678 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6678	likely pathogenic
REVEL	0.505	indeterminate
SaProt	LLR -11.25	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 7.6	GERP 0.71, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 40 kb · p 0.0011 · regional, not allelic
Overall
CADD	26.3	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 0.00167% Admixed American · 1/60,002 alleles

Overall 0.000124% 2/1,614,050 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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: DIS3L
Protein: p.Pro712Ser
Coding: c.2134C>T
MANE Select: NM_001143688
Type: single nucleotide variant
Location: chr15:66326297 (GRCh38)
Gene constraint: LOEUF 0.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.28 · 4 PDB
Residue 712: the rnb domain

Full DIS3L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DIS3L p.Ala146Thr Uncertain significance ★ ⚠ same type
DIS3L p.Ala362Val Uncertain significance ★ ⚠ same type
DIS3L p.Ala593Val Uncertain significance ★ ⚠ same type
DIS3L p.Ala693Thr Uncertain significance ★ ⚠ same type
DIS3L p.Ala740Ser Uncertain significance ★ ⚠ same type
DIS3L p.Ala740Val Uncertain significance ★ same type
DIS3L p.Arg1026His Uncertain significance ★ ⚠ same type
DIS3L p.Arg1026Pro 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/dis3l-p-pro712ser (accessed [today's date]).

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