Is FASN p.Pro2226= (c.6678G>A) pathogenic?

FASN p.Pro2226= (c.6678G>A) is classified Likely benign in FASN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-21). Very rare (popmax 0.00933%, afr); Associated with Epileptic encephalopathy.

What condition is associated with FASN p.Pro2226= (c.6678G>A)?

FASN p.Pro2226= (c.6678G>A) is associated with Epileptic encephalopathy (ClinVar).

How common is FASN p.Pro2226= (c.6678G>A) in the general population?

FASN p.Pro2226= (c.6678G>A) is very rare (popmax 0.00933%, afr) (gnomAD).

FASN p.Pro2226=

c.6678G>A · rs762791524 · VCV662123

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00933%, afr)

Conditions

Epileptic encephalopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.1	GERP -3.2
Overall
CADD	0.98	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00933% African / African-American · 7/75,034 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.00372% 60/1,610,960 alleles · very rare exomes 57/1,458,626 · genomes 3/152,334 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00933%	10,719
Admixed American	0.00502%	19,905
European (non-Finnish)	0.0039%	25,640
Remaining individualsnot grpmax-eligible	0.00321%	31,189
East Asian	0.00223%	44,838
South Asian	0.0011%	90,646

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: FASN
Protein: p.Pro2226=
Coding: c.6678G>A
MANE Select: NM_004104
dbSNP: rs762791524
Type: single nucleotide variant
Location: chr17:82080840 (GRCh38)
Gene constraint: LOEUF 0.284 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.65 · 34 PDB
Residue 2226: the 'thioesterase' region

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

Disease context

Epileptic encephalopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FASN c.3733-3C>T Uncertain significance ★★ same condition
FASN c.655+3G>T Uncertain significance ★★ same condition
FASN p.Ala1073Ser Uncertain significance ★★ ⚠ same condition
FASN p.Ala1272Val Uncertain significance ★★ ⚠ same condition
FASN p.Ala1285Val Uncertain significance ★★ ⚠ same condition
FASN p.Ala1569Ser Uncertain significance ★★ ⚠ same condition
FASN p.Ala1684Thr Uncertain significance ★★ same condition
FASN p.Ala1686Thr 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/fasn-p-pro2226 (accessed [today's date]).

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