Is SLC6A4 p.Ser293Phe (c.878C>T) pathogenic?

SLC6A4 p.Ser293Phe (c.878C>T) is classified Uncertain significance in SLC6A4 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-27). AlphaMissense: likely benign (0.0531); Rare (popmax 0.39%, eas); Associated with Behavior disorder.

What condition is associated with SLC6A4 p.Ser293Phe (c.878C>T)?

SLC6A4 p.Ser293Phe (c.878C>T) is associated with Behavior disorder (ClinVar).

How common is SLC6A4 p.Ser293Phe (c.878C>T) in the general population?

SLC6A4 p.Ser293Phe (c.878C>T) is rare (popmax 0.39%, eas) (gnomAD).

What do computational predictors say about SLC6A4 p.Ser293Phe (c.878C>T)?

AlphaMissense predicts likely benign (score 0.0531) — an in-silico prediction, not a clinical call.

SLC6A4 p.Ser293Phe

c.878C>T · rs199909202 · VCV889327

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0531 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.39%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Behavior disorder

Computational evidence

Protein change
AlphaMissense	0.0531	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -3.81	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 2.1	GERP -2.3, phastCons 0.22
Regional constraint	o/e 0.73	unconstrained · MANE · 23 kb · p 3.5e-14 · regional, not allelic
Overall
CADD	14.59	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 0.39% East Asian · 174/44,574 alleles

Filtering AF 0.343% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.325%

Overall 0.0167% 269/1,609,164 alleles · rare exomes 249/1,457,866 · genomes 20/151,298 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.39%	256
South Asian	0.0561%	1,784
Remaining individualsnot grpmax-eligible	0.0386%	2,593
Admixed American	0.00167%	59,774
European (non-Finnish)	0.00161%	61,956

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: SLC6A4
Protein: p.Ser293Phe
Coding: c.878C>T
MANE Select: NM_001045
dbSNP: rs199909202
Type: single nucleotide variant
Location: chr17:30216176 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 293: an α-helix

Full SLC6A4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Behavior disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SLC6A4 c.*1727C>T Uncertain significance ★★ same condition
SLC6A4 p.Val283Leu Uncertain significance ★★ ⚠ same condition
SLC6A4 c.*2160G>T Benign ★★ same condition
SLC6A4 c.*2353A>G Benign ★★ same condition
SLC6A4 c.*2389A>G Benign ★★ same condition
SLC6A4 c.*2957C>T Benign ★★ same condition
SLC6A4 c.*328A>G Likely benign ★★ same condition
SLC6A4 c.*3448G>C Likely benign ★★ 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/slc6a4-p-ser293phe (accessed [today's date]).

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