Is DONSON p.Asp516His (c.1546G>C) pathogenic?

DONSON p.Asp516His (c.1546G>C) is classified Likely benign in DONSON (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1162); Rare (popmax 0.239%, sas).

How common is DONSON p.Asp516His (c.1546G>C) in the general population?

DONSON p.Asp516His (c.1546G>C) is rare (popmax 0.239%, sas) (gnomAD).

What do computational predictors say about DONSON p.Asp516His (c.1546G>C)?

AlphaMissense predicts likely benign (score 0.1162) — an in-silico prediction, not a clinical call.

DONSON p.Asp516His

c.1546G>C · rs145014824 · VCV1565140

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1162 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.239%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1162	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -7.19	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 -0.05	GERP -0.61
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.95 · regional, not allelic
Overall
CADD	14.19	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 0.239% South Asian · 216/90,328 alleles

Filtering AF 0.213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.203%

Overall 0.132% 2,114/1,604,828 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.239%	418
European (non-Finnish)	0.151%	663
Remaining individualsnot grpmax-eligible	0.134%	748
Admixed American	0.0369%	2,709
Middle Eastern	0.0333%	3,000
Finnishnot grpmax-eligible	0.0157%	6,375
African / African-American	0.0134%	7,489

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.Asp516His
Coding: c.1546G>C
MANE Select: NM_017613
dbSNP: rs145014824
Type: single nucleotide variant
Location: chr21:33579367 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.94
Residue 516: a UniProt-annotated variant site (in missla)

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

Similar variants

DONSON c.1047-9A>G Pathogenic ★★ same type
DONSON c.1563+1G>T Pathogenic ★★ same type
DONSON p.Arg293Ter Pathogenic ★★ same type
DONSON p.Arg442Ter Pathogenic ★★ same type
DONSON p.Gln428Ter Pathogenic/Likely pathogenic ★★ same type
DONSON p.Phe165Ser Pathogenic/Likely pathogenic ★★ same type
DONSON p.Ala32Gly Uncertain significance ★★ ⚠ same type
DONSON p.Ala429Glu 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/donson-p-asp516his (accessed [today's date]).

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