Is FA2H p.Leu77= (c.229C>T) pathogenic?

FA2H p.Leu77= (c.229C>T) is classified Benign in FA2H (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-04). Common (popmax 44.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary spastic paraplegia 35.

What condition is associated with FA2H p.Leu77= (c.229C>T)?

FA2H p.Leu77= (c.229C>T) 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.Leu77=

Q: How common is FA2H p.Leu77= (c.229C>T) in the general population?

FA2H p.Leu77= (c.229C>T) is common (popmax 44.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.229C>T · rs929881 · VCV129028

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Common

common (popmax 44.1%, 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.6	GERP -0.75, phastCons 1
Overall
CADD	13.19	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 44.1% African / African-American · 31,727/71,922 alleles

Filtering AF 43.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 43.5%

Overall 30.5% 470,429/1,544,230 alleles · common exomes 421,292/1,392,126 · genomes 49,137/152,104 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	44.1%	2
Ashkenazi Jewishnot grpmax-eligible	37.1%	3
Middle Eastern	32.8%	3
European (non-Finnish)	31.9%	3
Remaining individualsnot grpmax-eligible	30.2%	3
Amishnot grpmax-eligible	27.9%	4
Finnishnot grpmax-eligible	25.2%	4
Admixed American	22.2%	4
South Asian	17.7%	6
East Asian	4.42%	23

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.Leu77=
Coding: c.229C>T
MANE Select: NM_024306
dbSNP: rs929881
Type: single nucleotide variant
Location: chr16:74774527 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 77: the cytochrome b5 heme-binding 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-leu77 (accessed [today's date]).

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