Is DUS2 p.Leu414Ser (c.1241T>C) pathogenic?

DUS2 p.Leu414Ser (c.1241T>C) is classified Uncertain significance in DUS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely benign (0.1547); Ultra-rare (popmax 0.0164%, mid).

How common is DUS2 p.Leu414Ser (c.1241T>C) in the general population?

DUS2 p.Leu414Ser (c.1241T>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about DUS2 p.Leu414Ser (c.1241T>C)?

AlphaMissense predicts likely benign (score 0.1547) — an in-silico prediction, not a clinical call.

DUS2 p.Leu414Ser

c.1241T>C · VCV3505775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1547 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1547	likely benign
REVEL	0.441	indeterminate
SaProt	LLR -0.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 41 kb · p 0.0097 · regional, not allelic
Overall
CADD	22.5	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00455%

Overall 0.00502% 81/1,613,830 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.00667%	15,003
European (non-Finnish)	0.0061%	16,389
Remaining individualsnot grpmax-eligible	0.0032%	31,242
African / African-American	0.00267%	37,463

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: DUS2
Protein: p.Leu414Ser
Coding: c.1241T>C
MANE Select: NM_017803
Type: single nucleotide variant
Location: chr16:68078515 (GRCh38)
Gene constraint: LOEUF 0.875 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.81 · 11 PDB
Residue 414: the drbm domain; a β-strand

Full DUS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DUS2 p.Ala181Thr Uncertain significance ★ ⚠ same type
DUS2 p.Ala244Gly Uncertain significance ★ ⚠ same type
DUS2 p.Ala271Val Uncertain significance ★ ⚠ same type
DUS2 p.Ala336Thr Uncertain significance ★ ⚠ same type
DUS2 p.Ala346Val Uncertain significance ★ ⚠ same type
DUS2 p.Ala36Val Uncertain significance ★ ⚠ same type
DUS2 p.Ala425Val Uncertain significance ★ ⚠ same type
DUS2 p.Arg101Thr 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/dus2-p-leu414ser (accessed [today's date]).

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