Is DIS3 p.Lys322Arg (c.965A>G) pathogenic?

DIS3 p.Lys322Arg (c.965A>G) is classified Uncertain significance in DIS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-19). AlphaMissense: likely benign (0.0773); Ultra-rare (popmax 0.0453%, afr).

How common is DIS3 p.Lys322Arg (c.965A>G) in the general population?

DIS3 p.Lys322Arg (c.965A>G) is ultra-rare (popmax 0.0453%, afr) (gnomAD).

What do computational predictors say about DIS3 p.Lys322Arg (c.965A>G)?

AlphaMissense predicts likely benign (score 0.0773) — an in-silico prediction, not a clinical call.

DIS3 p.Lys322Arg

c.965A>G · rs372266784 · VCV2366370

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0773 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0453%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0773	likely benign
REVEL	0.007	strongly benign-leaning
SaProt	LLR -6.90	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 1	GERP -0.88, phastCons 0.23
Regional constraint	o/e 0.94	unconstrained · MANE · 18 kb · p 0.072 · regional, not allelic
Overall
CADD	15.38	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 0.0453% African / African-American · 34/75,026 alleles

Filtering AF 0.0333% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0292%

Overall 0.00279% 45/1,613,348 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0453%	2,207
Admixed American	0.01%	9,989
Remaining individualsnot grpmax-eligible	0.0064%	15,618
European (non-Finnish)	8.48e-05%	1,179,581

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.Lys322Arg
Coding: c.965A>G
MANE Select: NM_014953
dbSNP: rs372266784
Type: single nucleotide variant
Location: chr13:72775233 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.12 · 3 PDB

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-lys322arg (accessed [today's date]).

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