Is DONSON p.Leu306Phe (c.916C>T) pathogenic?

DONSON p.Leu306Phe (c.916C>T) is classified Uncertain significance in DONSON (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-01). AlphaMissense: likely benign (0.1189); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with DONSON p.Leu306Phe (c.916C>T)?

DONSON p.Leu306Phe (c.916C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DONSON p.Leu306Phe (c.916C>T) in the general population?

DONSON p.Leu306Phe (c.916C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about DONSON p.Leu306Phe (c.916C>T)?

AlphaMissense predicts likely benign (score 0.1189) — an in-silico prediction, not a clinical call.

DONSON p.Leu306Phe

c.916C>T · rs756425637 · VCV1502855

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1189 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1189	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -10.04	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 1.2	GERP 2, phastCons 0.74
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.95 · regional, not allelic
Overall
CADD	14.39	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 0.00446% East Asian · 2/44,848 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.00031% 5/1,613,808 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,424
European (non-Finnish)	0.000254%	393,323

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: DONSON
Protein: p.Leu306Phe
Coding: c.916C>T
MANE Select: NM_017613
dbSNP: rs756425637
Type: single nucleotide variant
Location: chr21:33583536 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.94
Residue 306: a UniProt-annotated variant site (in missla)

Full DONSON 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

Similar variants

DONSON p.Leu306fs Pathogenic ★ same residue
DONSON p.Arg442Ter Pathogenic ★★ same condition
DONSON p.Gln428Ter Pathogenic/Likely pathogenic ★★ same condition
DONSON p.Ala32Gly Uncertain significance ★★ ⚠ same condition
DONSON p.Ala429Glu Uncertain significance ★★ ⚠ same condition
DONSON p.Arg162Gln Uncertain significance ★★ ⚠ same condition
DONSON p.Arg234His Uncertain significance ★★ ⚠ same condition
DONSON p.Arg239Ser Uncertain significance ★★ ⚠ 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/donson-p-leu306phe (accessed [today's date]).

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