Is FA2H p.Ile281= (c.843C>T) pathogenic?

FA2H p.Ile281= (c.843C>T) is classified Likely benign in FA2H (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-01). Ultra-rare (popmax 0.0292%, eas); Associated with Spastic paraplegia.

What condition is associated with FA2H p.Ile281= (c.843C>T)?

FA2H p.Ile281= (c.843C>T) is associated with Spastic paraplegia (ClinVar).

How common is FA2H p.Ile281= (c.843C>T) in the general population?

FA2H p.Ile281= (c.843C>T) is ultra-rare (popmax 0.0292%, eas) (gnomAD).

FA2H p.Ile281=

c.843C>T · rs544646155 · VCV2712050

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0292%, eas)

Conditions

Spastic paraplegia

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 -2	GERP -2.9
Overall
CADD	1.776	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0292% East Asian · 13/44,522 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00168% 27/1,606,892 alleles · ultra-rare exomes 23/1,454,882 · genomes 4/152,010 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0292%	3,425
Middle Eastern	0.0165%	6,050
Remaining individualsnot grpmax-eligible	0.00643%	15,556
Admixed American	0.00341%	29,335
South Asian	0.00333%	30,065
African / African-American	0.00134%	74,880
European (non-Finnish)	0.000255%	392,311

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: FA2H
Protein: p.Ile281=
Coding: c.843C>T
MANE Select: NM_024306
dbSNP: rs544646155
Type: single nucleotide variant
Location: chr16:74716543 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 281: the fatty acid hydroxylase domain

Full FA2H gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FA2H c.506+1G>C Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Arg269His Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Met1Val Pathogenic ★★ same condition
FA2H p.Pro44Gln Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Pro44Ser Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Arg269Cys Uncertain significance ★★ ⚠ same condition
FA2H p.Glu365Gln Uncertain significance ★★ ⚠ same condition
FA2H p.Gly258Ser 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/fa2h-p-ile281 (accessed [today's date]).

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