Is DCST2 p.Phe516Ser (c.1547T>C) pathogenic?

DCST2 p.Phe516Ser (c.1547T>C) is classified Uncertain significance in DCST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-29). AlphaMissense: likely benign (0.1144); Very rare (popmax 0.00297%, nfe).

How common is DCST2 p.Phe516Ser (c.1547T>C) in the general population?

DCST2 p.Phe516Ser (c.1547T>C) is very rare (popmax 0.00297%, nfe) (gnomAD).

What do computational predictors say about DCST2 p.Phe516Ser (c.1547T>C)?

AlphaMissense predicts likely benign (score 0.1144) — an in-silico prediction, not a clinical call.

DCST2 p.Phe516Ser

c.1547T>C · rs765629301 · VCV2522623

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1144 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00297%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1144	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR -6.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1	GERP 0.42, phastCons 0.027
Regional constraint	o/e 0.94	unconstrained · MANE · 15 kb · p 0.075 · regional, not allelic
Overall
CADD	16.82	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 0.00297% European (non-Finnish) · 35/1,180,036 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00235% 38/1,613,754 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00297%	33,715
East Asian	0.00223%	44,890
Remaining individualsnot grpmax-eligible	0.0016%	62,480
African / African-American	0.00133%	74,930

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: DCST2
Protein: p.Phe516Ser
Coding: c.1547T>C
MANE Select: NM_144622
dbSNP: rs765629301
Type: single nucleotide variant
Location: chr1:155026366 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.49

Full DCST2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DCST2 p.Ala135Thr Uncertain significance ★ ⚠ same type
DCST2 p.Ala141Thr Uncertain significance ★ ⚠ same type
DCST2 p.Ala20Thr Uncertain significance ★ ⚠ same type
DCST2 p.Ala341Val Uncertain significance ★ ⚠ same type
DCST2 p.Ala39Thr Uncertain significance ★ ⚠ same type
DCST2 p.Ala597Asp Uncertain significance ★ ⚠ same type
DCST2 p.Ala668Val Uncertain significance ★ ⚠ same type
DCST2 p.Ala670Val 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/dcst2-p-phe516ser (accessed [today's date]).

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