Is DIS3 p.Leu247Phe (c.739C>T) pathogenic?

DIS3 p.Leu247Phe (c.739C>T) is classified Uncertain significance in DIS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely benign (0.0729); Very rare (popmax 0.00336%, amr).

How common is DIS3 p.Leu247Phe (c.739C>T) in the general population?

DIS3 p.Leu247Phe (c.739C>T) is very rare (popmax 0.00336%, amr) (gnomAD).

What do computational predictors say about DIS3 p.Leu247Phe (c.739C>T)?

AlphaMissense predicts likely benign (score 0.0729) — an in-silico prediction, not a clinical call.

DIS3 p.Leu247Phe

c.739C>T · rs771392558 · VCV2244437

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0729 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00336%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0729	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -9.18	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 5.2	GERP 0.37, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 18 kb · p 0.072 · regional, not allelic
Overall
CADD	20.1	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 0.00336% Admixed American · 2/59,574 alleles

Filtering AF 0.000557% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000208%

Overall 0.000248% 4/1,611,268 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00336%	29,787
Remaining individualsnot grpmax-eligible	0.0016%	62,374
European (non-Finnish)	8.48e-05%	1,179,103

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.Leu247Phe
Coding: c.739C>T
MANE Select: NM_014953
dbSNP: rs771392558
Type: single nucleotide variant
Location: chr13:72776008 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.12 · 3 PDB
Residue 247: the csd1 domain; a β-strand

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-leu247phe (accessed [today's date]).

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