Is FA2H p.Pro97Ala (c.289C>G) pathogenic?

FA2H p.Pro97Ala (c.289C>G) is classified Benign/Likely benign in FA2H (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0456); Common (popmax 5.26%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Spastic paraplegia.

What condition is associated with FA2H p.Pro97Ala (c.289C>G)?

FA2H p.Pro97Ala (c.289C>G) is associated with Spastic paraplegia, hereditary spastic paraplegia 35, hereditary spastic paraplegia (ClinVar).

What do computational predictors say about FA2H p.Pro97Ala (c.289C>G)?

AlphaMissense predicts likely benign (score 0.0456) — an in-silico prediction, not a clinical call.

FA2H p.Pro97Ala

Q: How common is FA2H p.Pro97Ala (c.289C>G) in the general population?

FA2H p.Pro97Ala (c.289C>G) is common (popmax 5.26%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.289C>G · rs35874850 · VCV129029

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0456 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.26%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0456	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -6.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.71	GERP -2
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.86 · regional, not allelic
Overall
CADD	0.204	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 5.26% African / African-American · 3,941/74,952 alleles

Filtering AF 5.12% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.07%

Overall 0.852% 13,750/1,613,458 alleles · common exomes 10,792/1,461,240 · genomes 2,958/152,218 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.26%	19
Middle Eastern	1.48%	67
Remaining individualsnot grpmax-eligible	1%	100
Admixed American	0.81%	124
European (non-Finnish)	0.663%	151
Finnishnot grpmax-eligible	0.45%	222
South Asian	0.434%	231
Ashkenazi Jewishnot grpmax-eligible	0.351%	285
East Asian	0.00892%	11,216

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.Pro97Ala
Coding: c.289C>G
MANE Select: NM_024306
dbSNP: rs35874850
Type: single nucleotide variant
Location: chr16:74740097 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 97: a UniProt-annotated variant site (in)

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

Disease context

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

Also linked: hereditary spastic paraplegia 35 hereditary spastic paraplegia

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-pro97ala (accessed [today's date]).

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