Is FA2H p.Ile229= (c.687C>T) pathogenic?

FA2H p.Ile229= (c.687C>T) is classified Likely benign in FA2H (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-06). Ultra-rare (popmax 0.0164%, mid); Associated with Spastic paraplegia.

What condition is associated with FA2H p.Ile229= (c.687C>T)?

FA2H p.Ile229= (c.687C>T) is associated with Spastic paraplegia (ClinVar).

How common is FA2H p.Ile229= (c.687C>T) in the general population?

FA2H p.Ile229= (c.687C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

FA2H p.Ile229=

c.687C>T · VCV3605828

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

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 -16	GERP -3.5
Overall
CADD	0.082	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00815% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00297% 48/1,613,930 alleles · ultra-rare exomes 42/1,461,712 · genomes 6/152,218 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.0147%	6,812
European (non-Finnish)	0.00288%	34,707
Remaining individualsnot grpmax-eligible	0.0016%	62,488
South Asian	0.0011%	91,094

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.Ile229=
Coding: c.687C>T
MANE Select: NM_024306
Type: single nucleotide variant
Location: chr16:74719087 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 229: 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 p.Ile229del Uncertain significance ★ same residue
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

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-ile229 (accessed [today's date]).

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