Is FKBP14 p.Leu211Ser (c.632T>C) pathogenic?

FKBP14 p.Leu211Ser (c.632T>C) is classified Uncertain significance in FKBP14 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-19). AlphaMissense: likely pathogenic (0.9921); Very rare (popmax 0.000854%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with FKBP14 p.Leu211Ser (c.632T>C)?

FKBP14 p.Leu211Ser (c.632T>C) is associated with Cardiovascular phenotype, Ehlers-Danlos syndrome, kyphoscoliotic type, 2 (ClinVar).

How common is FKBP14 p.Leu211Ser (c.632T>C) in the general population?

FKBP14 p.Leu211Ser (c.632T>C) is very rare (popmax 0.000854%, nfe) (gnomAD).

What do computational predictors say about FKBP14 p.Leu211Ser (c.632T>C)?

AlphaMissense predicts likely pathogenic (score 0.9921) — an in-silico prediction, not a clinical call.

FKBP14 p.Leu211Ser

c.632T>C · rs1252646088 · VCV1904530

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9921 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000854%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9921	likely pathogenic · top 3% in FKBP14
REVEL	0.559	indeterminate
SaProt	LLR -10.12	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 12 kb · p 0.8 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000854% European (non-Finnish) · 10/1,171,248 alleles

Filtering AF 0.000432% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000315%

Overall 0.000628% 10/1,591,212 alleles · very rare exomes 10/1,438,884 · genomes 0/152,328 · joint denominator

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: FKBP14
Protein: p.Leu211Ser
Coding: c.632T>C
MANE Select: NM_017946
dbSNP: rs1252646088
Type: single nucleotide variant
Location: chr7:30014739 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.27 · 2 PDB
Residue 211: the ef-hand 2 domain

Full FKBP14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ehlers-Danlos syndrome, kyphoscoliotic type, 2

Similar variants

FKBP14 p.Ser143Ter Pathogenic/Likely pathogenic ★★ same condition
FKBP14 c.198-3T>C Uncertain significance ★★ same condition
FKBP14 p.Arg135Gln Uncertain significance ★★ ⚠ same condition
FKBP14 p.Arg2Ser Uncertain significance ★★ ⚠ same condition
FKBP14 p.Asp181Glu Uncertain significance ★★ ⚠ same condition
FKBP14 p.Asp46Gly Uncertain significance ★★ ⚠ same condition
FKBP14 p.Asp46Tyr Uncertain significance ★★ ⚠ same condition
FKBP14 p.Glu99Gln 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/fkbp14-p-leu211ser (accessed [today's date]).

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