Is BTD p.Ser2Phe (c.5C>T) pathogenic?

BTD p.Ser2Phe (c.5C>T) is classified Uncertain significance in BTD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-05). AlphaMissense: likely benign (0.1267); Very rare (popmax 0.00801%, afr); Associated with Inborn genetic diseases.

What condition is associated with BTD p.Ser2Phe (c.5C>T)?

BTD p.Ser2Phe (c.5C>T) is associated with Inborn genetic diseases (ClinVar).

How common is BTD p.Ser2Phe (c.5C>T) in the general population?

BTD p.Ser2Phe (c.5C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about BTD p.Ser2Phe (c.5C>T)?

AlphaMissense predicts likely benign (score 0.1267) — an in-silico prediction, not a clinical call.

BTD p.Ser2Phe

c.5C>T · rs754794170 · VCV2609987

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1267 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1267	likely benign
REVEL	0.296	indeterminate
SaProt	LLR -7.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.45, phastCons 0.036
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	16.67	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S22F vs ClinVar S2F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,932 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.000434% 7/1,614,106 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,489
European (non-Finnish)	8.47e-05%	1,180,050

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: BTD
Protein: p.Ser2Phe
Coding: c.5C>T
MANE Select: NM_001370658
dbSNP: rs754794170
Type: single nucleotide variant
Location: chr3:15635444 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77

Full BTD 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

BTD p.Gly94Val Pathogenic/Likely pathogenic ★★ same condition
BTD p.His465Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
BTD p.Asn152Ser Uncertain significance ★★ ⚠ same condition
BTD p.Asp304Glu Uncertain significance ★★ ⚠ same condition
BTD p.Asp348Ala Uncertain significance ★★ ⚠ same condition
BTD p.Cys351Arg Uncertain significance ★★ ⚠ same condition
BTD p.Gln68His Uncertain significance ★★ ⚠ same condition
BTD p.Gly273Arg 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/btd-p-ser2phe (accessed [today's date]).

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