Is FA2H p.Pro129Ser (c.385C>T) pathogenic?

FA2H p.Pro129Ser (c.385C>T) is classified Uncertain significance in FA2H (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely pathogenic (0.6944); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 35.

What condition is associated with FA2H p.Pro129Ser (c.385C>T)?

FA2H p.Pro129Ser (c.385C>T) is associated with hereditary spastic paraplegia 35 (ClinVar).

How common is FA2H p.Pro129Ser (c.385C>T) in the general population?

FA2H p.Pro129Ser (c.385C>T) 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.Pro129Ser (c.385C>T)?

AlphaMissense predicts likely pathogenic (score 0.6944) — an in-silico prediction, not a clinical call.

FA2H p.Pro129Ser

c.385C>T · rs886052291 · VCV320500

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6944 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 35

Computational evidence

Protein change
AlphaMissense	0.6944	likely pathogenic
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -12.69	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.86 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Pro129Ser
Coding: c.385C>T
MANE Select: NM_024306
dbSNP: rs886052291
Type: single nucleotide variant
Location: chr16:74727365 (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

FAAH p.Pro129Thr Benign/Likely benign ★★ ⚠ 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.Arg235His 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-pro129ser (accessed [today's date]).

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