Is FA2H p.Val296= (c.888A>G) pathogenic?

FA2H p.Val296= (c.888A>G) is classified Benign/Likely benign in FA2H (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 22.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary spastic paraplegia 35.

What condition is associated with FA2H p.Val296= (c.888A>G)?

FA2H p.Val296= (c.888A>G) is associated with hereditary spastic paraplegia 35, hereditary spastic paraplegia (ClinVar).

How is Autosomal recessive spastic paraplegia type 35 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

FA2H p.Val296=

Q: How common is FA2H p.Val296= (c.888A>G) in the general population?

FA2H p.Val296= (c.888A>G) is common (popmax 22.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.888A>G · rs11554621 · VCV129032

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 22.1%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary spastic paraplegia 35

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 0.59	GERP -0.59, phastCons 1
Overall
CADD	9.883	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 22.1% African / African-American · 16,545/74,816 alleles

Filtering AF 21.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.7%

Overall 14.5% 234,587/1,613,310 alleles · common exomes 211,319/1,461,584 · genomes 23,268/151,726 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	22.1%	5
European (non-Finnish)	16%	6
Remaining individualsnot grpmax-eligible	14%	7
Amishnot grpmax-eligible	13.5%	7
Middle Eastern	12.6%	8
Ashkenazi Jewishnot grpmax-eligible	10.4%	10
Admixed American	9%	11
Finnishnot grpmax-eligible	6.24%	16
South Asian	6.1%	16
East Asian	4.19%	24

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.Val296=
Coding: c.888A>G
MANE Select: NM_024306
dbSNP: rs11554621
Type: single nucleotide variant
Location: chr16:74716498 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 296: the fatty acid hydroxylase domain

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

Disease context

hereditary spastic paraplegia 35 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia

For Autosomal recessive spastic paraplegia type 35 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

Similar variants

FA2H c.363+2T>C Pathogenic/Likely pathogenic ★★ same condition
FA2H c.506+1G>C Pathogenic/Likely pathogenic ★★ same condition
FA2H c.786+1G>A Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Arg127Ter Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Arg189Ter Pathogenic ★★ same condition
FA2H p.Arg197Ter Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Arg235His Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Arg269His Pathogenic/Likely pathogenic ★★ 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-val296 (accessed [today's date]).

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