Is FCSK p.Ala652Val (c.1955C>T) pathogenic?

FCSK p.Ala652Val (c.1955C>T) is classified Uncertain significance in FCSK (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.0976); Rare (popmax 0.132%, mid); Associated with congenital disorder of glycosylation with defective fucosylation 2.

What condition is associated with FCSK p.Ala652Val (c.1955C>T)?

FCSK p.Ala652Val (c.1955C>T) is associated with congenital disorder of glycosylation with defective fucosylation 2 (ClinVar).

How common is FCSK p.Ala652Val (c.1955C>T) in the general population?

FCSK p.Ala652Val (c.1955C>T) is rare (popmax 0.132%, mid) (gnomAD).

What do computational predictors say about FCSK p.Ala652Val (c.1955C>T)?

AlphaMissense predicts likely benign (score 0.0976) — an in-silico prediction, not a clinical call.

FCSK p.Ala652Val

c.1955C>T · rs201433219 · VCV1031186

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0976 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital disorder of glycosylation with defective fucosylation 2

Computational evidence

Protein change
AlphaMissense	0.0976	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -9.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.3	GERP 1.6, phastCons 0.98
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.027 · regional, not allelic
Overall
CADD	19.23	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 0.132% Middle Eastern · 8/6,060 alleles

Filtering AF 0.0657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0479%

Overall 0.0129% 208/1,613,554 alleles · rare exomes 189/1,461,230 · genomes 19/152,324 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	758
Ashkenazi Jewishnot grpmax-eligible	0.101%	986
South Asian	0.0187%	5,356
European (non-Finnish)	0.0121%	8,251
Remaining individualsnot grpmax-eligible	0.0112%	8,924
African / African-American	0.00266%	37,531
Admixed American	0.00167%	59,972

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: FCSK
Protein: p.Ala652Val
Coding: c.1955C>T
MANE Select: NM_145059
dbSNP: rs201433219
Type: single nucleotide variant
Location: chr16:70474306 (GRCh38)
Gene constraint: LOEUF 1.254 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.20

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

Disease context

congenital disorder of glycosylation with defective fucosylation 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FCSK p.Ala652= Likely benign ★ same residue
FCSK c.412-2A>G Likely pathogenic ★★ same condition
FCSK p.Ala558Val Uncertain significance ★★ ⚠ same condition
FCSK p.Arg32Trp Uncertain significance ★★ ⚠ same condition
FCSK p.Arg527Cys Uncertain significance ★★ ⚠ same condition
FCSK p.Arg547Gln Uncertain significance ★★ ⚠ same condition
FCSK p.Arg605Trp Uncertain significance ★★ same condition
FCSK p.Arg74Gln 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/fcsk-p-ala652val (accessed [today's date]).

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