Is DIS3L2 p.Phe404Ile (c.1210T>A) pathogenic?

DIS3L2 p.Phe404Ile (c.1210T>A) is classified Uncertain significance in DIS3L2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-11). AlphaMissense: likely benign (0.2325); Very rare (popmax 0.00668%, eas); Associated with Inborn genetic diseases.

What condition is associated with DIS3L2 p.Phe404Ile (c.1210T>A)?

DIS3L2 p.Phe404Ile (c.1210T>A) is associated with Inborn genetic diseases, Perlman syndrome (ClinVar).

How common is DIS3L2 p.Phe404Ile (c.1210T>A) in the general population?

DIS3L2 p.Phe404Ile (c.1210T>A) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about DIS3L2 p.Phe404Ile (c.1210T>A)?

AlphaMissense predicts likely benign (score 0.2325) — an in-silico prediction, not a clinical call.

DIS3L2 p.Phe404Ile

c.1210T>A · rs771992590 · VCV1004308

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2325 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2325	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -11.27	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 319 kb · p 0.024 · regional, not allelic
Overall
CADD	23.5	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 0.00668% East Asian · 3/44,886 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000186% 3/1,613,900 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: DIS3L2
Protein: p.Phe404Ile
Coding: c.1210T>A
MANE Select: NM_152383
dbSNP: rs771992590
Type: single nucleotide variant
Location: chr2:232238538 (GRCh38)
Gene constraint: LOEUF 0.468 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 83.26 · 4 PDB
Residue 404: a β-strand

Full DIS3L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Perlman syndrome

Similar variants

DIS3L2 p.Phe404Leu Uncertain significance ★ ⚠ same residue
DIS3L2 c.1740-1G>C Likely pathogenic ★★ same condition
DIS3L2 p.Arg245Ter Pathogenic/Likely pathogenic ★★ same condition
DIS3L2 p.Arg388Ter Pathogenic/Likely pathogenic ★★ same condition
DIS3L2 p.Arg43Ter Pathogenic/Likely pathogenic ★★ same condition
DIS3L2 p.Arg724Ter Pathogenic/Likely pathogenic ★★ same condition
DIS3L2 p.Gln604Ter Pathogenic ★★ same condition
DIS3L2 p.Glu332Ter Likely pathogenic ★★ same condition

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/dis3l2-p-phe404ile (accessed [today's date]).

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