Is FA2H p.Arg235Cys (c.703C>T) pathogenic?

FA2H p.Arg235Cys (c.703C>T) is classified Conflicting classifications of pathogenicity in FA2H (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-09-25). AlphaMissense: ambiguous (0.4235); Very rare (popmax 0.00133%, afr); Associated with hereditary spastic paraplegia 35.

What condition is associated with FA2H p.Arg235Cys (c.703C>T)?

FA2H p.Arg235Cys (c.703C>T) is associated with hereditary spastic paraplegia 35, intellectual disability (ClinVar).

How common is FA2H p.Arg235Cys (c.703C>T) in the general population?

FA2H p.Arg235Cys (c.703C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Autosomal recessive spastic paraplegia type 35 inherited?

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

What do computational predictors say about FA2H p.Arg235Cys (c.703C>T)?

AlphaMissense predicts ambiguous (score 0.4235) — an in-silico prediction, not a clinical call.

FA2H p.Arg235Cys

c.703C>T · rs387907039 · VCV30870

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4235 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary spastic paraplegia 35

Computational evidence

Protein change
AlphaMissense	0.4235	ambiguous
REVEL	0.845	moderately pathogenic-leaning
SaProt	LLR -14.55	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.86 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,936 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000867% 14/1,613,916 alleles · very rare exomes 12/1,461,712 · genomes 2/152,204 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
African / African-Americangrpmax	0.00133%	74,936
South Asian	0.0011%	91,088
European (non-Finnish)	0.000932%	107,276

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg235Cys
Coding: c.703C>T
MANE Select: NM_024306
dbSNP: rs387907039
Type: single nucleotide variant
Location: chr16:74719071 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 235: a UniProt-annotated variant site (in spg35; significantly reduced enzymatic function); 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: intellectual disability

For Autosomal recessive spastic paraplegia type 35 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

Similar variants

FA2H p.Arg235His Pathogenic/Likely pathogenic ★★ same residue
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.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-arg235cys (accessed [today's date]).

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