Is FKBP14 p.Pro25Arg (c.74C>G) pathogenic?

FKBP14 p.Pro25Arg (c.74C>G) is classified Uncertain significance in FKBP14 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-11). AlphaMissense: ambiguous (0.3441); Very rare (popmax 0.00432%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with FKBP14 p.Pro25Arg (c.74C>G)?

FKBP14 p.Pro25Arg (c.74C>G) is associated with Cardiovascular phenotype, Ehlers-Danlos syndrome, kyphoscoliotic type, 2 (ClinVar).

How common is FKBP14 p.Pro25Arg (c.74C>G) in the general population?

FKBP14 p.Pro25Arg (c.74C>G) is very rare (popmax 0.00432%, nfe) (gnomAD).

What do computational predictors say about FKBP14 p.Pro25Arg (c.74C>G)?

AlphaMissense predicts ambiguous (score 0.3441) — an in-silico prediction, not a clinical call.

FKBP14 p.Pro25Arg

c.74C>G · rs142423230 · VCV1507089

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3441 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00432%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3441	ambiguous
REVEL	0.142	moderately benign-leaning
SaProt	LLR -14.45	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 12 kb · p 0.8 · regional, not allelic
Overall
CADD	28.9	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 0.00432% European (non-Finnish) · 51/1,179,992 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00335% 54/1,614,016 alleles · very rare exomes 51/1,461,820 · genomes 3/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00432%	23,137
Remaining individualsnot grpmax-eligible	0.0032%	31,243
Admixed American	0.00167%	60,004

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.Pro25Arg
Coding: c.74C>G
MANE Select: NM_017946
dbSNP: rs142423230
Type: single nucleotide variant
Location: chr7:30026435 (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 25: an α-helix

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.Pro25= Likely benign ★ same residue
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

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-pro25arg (accessed [today's date]).

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