Is FA2H p.Lys121Arg (c.362A>G) pathogenic?

FA2H p.Lys121Arg (c.362A>G) is classified Likely pathogenic in FA2H (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-27). AlphaMissense: likely benign (0.0788); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 35.

What condition is associated with FA2H p.Lys121Arg (c.362A>G)?

FA2H p.Lys121Arg (c.362A>G) is associated with hereditary spastic paraplegia 35 (ClinVar).

How common is FA2H p.Lys121Arg (c.362A>G) in the general population?

FA2H p.Lys121Arg (c.362A>G) is absent from gnomAD v4.1 (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.Lys121Arg (c.362A>G)?

AlphaMissense predicts likely benign (score 0.0788) — an in-silico prediction, not a clinical call.

FA2H p.Lys121Arg

c.362A>G · VCV3776796

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0788 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary spastic paraplegia 35

Computational evidence

Protein change
AlphaMissense	0.0788	likely benign ⚠ discordant with ClinVar
REVEL	0.299	indeterminate
SaProt	LLR -3.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.53	donor loss, 1 bp away · masked 0 · deltas
Pangolin	Δ0.40	loss · gain 0.08 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.86 · regional, not allelic
Overall
CADD	25.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FA2H
Protein: p.Lys121Arg
Coding: c.362A>G
MANE Select: NM_024306
Type: single nucleotide variant
Location: chr16:74740024 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53

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

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-lys121arg (accessed [today's date]).

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