Is FKBP14 p.Leu49Phe (c.147G>C) pathogenic?

FKBP14 p.Leu49Phe (c.147G>C) is classified Uncertain significance in FKBP14 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-03). AlphaMissense: likely pathogenic (0.7183); Ultra-rare (popmax 0.0373%, sas); Associated with Ehlers-Danlos syndrome, kyphoscoliotic type, 2.

What condition is associated with FKBP14 p.Leu49Phe (c.147G>C)?

FKBP14 p.Leu49Phe (c.147G>C) is associated with Ehlers-Danlos syndrome, kyphoscoliotic type, 2 (ClinVar).

How common is FKBP14 p.Leu49Phe (c.147G>C) in the general population?

FKBP14 p.Leu49Phe (c.147G>C) is ultra-rare (popmax 0.0373%, sas) (gnomAD).

What do computational predictors say about FKBP14 p.Leu49Phe (c.147G>C)?

AlphaMissense predicts likely pathogenic (score 0.7183) — an in-silico prediction, not a clinical call.

FKBP14 p.Leu49Phe

c.147G>C · rs761481531 · VCV948776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7183 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Ehlers-Danlos syndrome, kyphoscoliotic type, 2

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.7183	likely pathogenic
REVEL	0.511	indeterminate
SaProt	LLR -7.29	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.2	GERP 0.63, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 12 kb · p 0.8 · regional, not allelic
Overall
CADD	22.9	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 0.0373% South Asian · 34/91,074 alleles

Filtering AF 0.0274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.024%

Overall 0.00223% 36/1,613,884 alleles · ultra-rare exomes 32/1,461,716 · genomes 4/152,168 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0373%	2,679
Remaining individualsnot grpmax-eligible	0.0016%	62,478
African / African-American	0.00134%	74,904

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.Leu49Phe
Coding: c.147G>C
MANE Select: NM_017946
dbSNP: rs761481531
Type: single nucleotide variant
Location: chr7:30026362 (GRCh38)

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

Disease context

Ehlers-Danlos syndrome, kyphoscoliotic type, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Kyphoscoliotic Ehlers-Danlos syndrome (Orphanet):

Onset: Antenatal, Neonatal

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-leu49phe (accessed [today's date]).

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