Is DSTYK p.Thr618Met (c.1853C>T) pathogenic?

DSTYK p.Thr618Met (c.1853C>T) is classified Uncertain significance in DSTYK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-14). AlphaMissense: likely benign (0.1878); Ultra-rare (popmax 0.0124%, nfe).

How common is DSTYK p.Thr618Met (c.1853C>T) in the general population?

DSTYK p.Thr618Met (c.1853C>T) is ultra-rare (popmax 0.0124%, nfe) (gnomAD).

What do computational predictors say about DSTYK p.Thr618Met (c.1853C>T)?

AlphaMissense predicts likely benign (score 0.1878) — an in-silico prediction, not a clinical call.

DSTYK p.Thr618Met

c.1853C>T · rs374722933 · VCV2167023

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1878 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0124%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1878	likely benign
REVEL	0.663	pathogenic-leaning
SaProt	LLR -5.50	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 54 kb · p 2.6e-11 · regional, not allelic
Overall
CADD	32.0	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 0.0124% European (non-Finnish) · 146/1,179,996 alleles

Filtering AF 0.0107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.01%

Overall 0.00973% 157/1,614,014 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0124%	8,082
Admixed American	0.00833%	11,999
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00267%	37,461
South Asian	0.0022%	45,541

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: DSTYK
Protein: p.Thr618Met
Coding: c.1853C>T
MANE Select: NM_015375
dbSNP: rs374722933
Type: single nucleotide variant
Location: chr1:205161353 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.02
Residue 618: a UniProt-annotated variant site (in cakut1; uncertain significance)

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

Similar variants

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DSTYK p.Ala601Val Uncertain significance ★★ ⚠ same type
DSTYK p.Arg411Gln Uncertain significance ★★ ⚠ same type
DSTYK p.Arg462Gln Uncertain significance ★★ ⚠ same type
DSTYK p.Arg471Gln Uncertain significance ★★ ⚠ same type
DSTYK p.Arg626Gln Uncertain significance ★★ ⚠ same type
DSTYK p.Arg635His 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/dstyk-p-thr618met (accessed [today's date]).

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