Is FUCA1 p.Pro224Ser (c.670C>T) pathogenic?

FUCA1 p.Pro224Ser (c.670C>T) is classified Uncertain significance in FUCA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely pathogenic (0.9236); Very rare (popmax 0.00804%, afr); Associated with Inborn genetic diseases.

What condition is associated with FUCA1 p.Pro224Ser (c.670C>T)?

FUCA1 p.Pro224Ser (c.670C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FUCA1 p.Pro224Ser (c.670C>T) in the general population?

FUCA1 p.Pro224Ser (c.670C>T) is very rare (popmax 0.00804%, afr) (gnomAD).

What do computational predictors say about FUCA1 p.Pro224Ser (c.670C>T)?

AlphaMissense predicts likely pathogenic (score 0.9236) — an in-silico prediction, not a clinical call.

FUCA1 p.Pro224Ser

c.670C>T · VCV4260580

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9236 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00804%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9236	likely pathogenic
REVEL	0.726	pathogenic-leaning
SaProt	LLR -12.93	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.86, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 23 kb · p 0.31 · regional, not allelic
Overall
CADD	28.4	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 0.00804% African / African-American · 6/74,660 alleles

Filtering AF 0.00348% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00239%

Overall 0.000437% 7/1,601,602 alleles · very rare exomes 3/1,449,478 · genomes 4/152,124 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00804%	12,443
Remaining individualsnot grpmax-eligible	0.00161%	62,024

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: FUCA1
Protein: p.Pro224Ser
Coding: c.670C>T
MANE Select: NM_000147
Type: single nucleotide variant
Location: chr1:23859896 (GRCh38)
Gene constraint: LOEUF 1.162 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.60 · 2 PDB

Full FUCA1 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

FUCA1 p.Ala368Thr Uncertain significance ★★ ⚠ same condition
FUCA1 p.Arg162Gln Uncertain significance ★★ ⚠ same condition
FUCA1 p.Arg162Trp Uncertain significance ★★ ⚠ same condition
FUCA1 p.Arg173Gln Uncertain significance ★★ ⚠ same condition
FUCA1 p.Arg178His Uncertain significance ★★ ⚠ same condition
FUCA1 p.Arg30Trp Uncertain significance ★★ ⚠ same condition
FUCA1 p.Arg9Trp Uncertain significance ★★ ⚠ same condition
FUCA1 p.Asp217Asn 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/fuca1-p-pro224ser (accessed [today's date]).

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