Is DIS3L p.Ser569Phe (c.1706C>T) pathogenic?

DIS3L p.Ser569Phe (c.1706C>T) is classified Uncertain significance in DIS3L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-08). AlphaMissense: likely benign (0.2336); Ultra-rare (popmax 0.0426%, afr).

How common is DIS3L p.Ser569Phe (c.1706C>T) in the general population?

DIS3L p.Ser569Phe (c.1706C>T) is ultra-rare (popmax 0.0426%, afr) (gnomAD).

What do computational predictors say about DIS3L p.Ser569Phe (c.1706C>T)?

AlphaMissense predicts likely benign (score 0.2336) — an in-silico prediction, not a clinical call.

DIS3L p.Ser569Phe

c.1706C>T · VCV3840168

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2336 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0426%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2336	likely benign
REVEL	0.283	benign-leaning
SaProt	LLR -9.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 40 kb · p 0.0011 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0426% African / African-American · 32/75,030 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0271%

Overall 0.00205% 33/1,612,598 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0426%	2,345
Remaining individualsnot grpmax-eligible	0.0016%	62,442

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.Ser569Phe
Coding: c.1706C>T
MANE Select: NM_001143688
Type: single nucleotide variant
Location: chr15:66325869 (GRCh38)
Gene constraint: LOEUF 0.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.28 · 4 PDB
Residue 569: the rnb domain; a β-strand

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

Similar variants

DIS3L p.Ser569Thr Uncertain significance ★ ⚠ same residue
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

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-ser569phe (accessed [today's date]).

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