Is FA2H p.Pro44Gln (c.131C>A) pathogenic?

FA2H p.Pro44Gln (c.131C>A) is classified Pathogenic/Likely pathogenic in FA2H (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-13). AlphaMissense: likely pathogenic (0.8796); Ultra-rare (popmax 0.0142%, amr); Associated with Spastic paraplegia.

What condition is associated with FA2H p.Pro44Gln (c.131C>A)?

FA2H p.Pro44Gln (c.131C>A) is associated with Spastic paraplegia, neurodegeneration with brain iron accumulation (ClinVar).

How common is FA2H p.Pro44Gln (c.131C>A) in the general population?

FA2H p.Pro44Gln (c.131C>A) is ultra-rare (popmax 0.0142%, amr) (gnomAD).

What do computational predictors say about FA2H p.Pro44Gln (c.131C>A)?

AlphaMissense predicts likely pathogenic (score 0.8796) — an in-silico prediction, not a clinical call.

FA2H p.Pro44Gln

c.131C>A · rs915291720 · VCV458305

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8796 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0142%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.8796	likely pathogenic ✓ concordant with ClinVar
REVEL	0.924	moderately pathogenic-leaning
SaProt	LLR -14.67	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 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.86 · regional, not allelic
Overall
CADD	33.0	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 0.0142% Admixed American · 7/49,124 alleles

Filtering AF 0.0066% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00469%

Overall 0.000594% 9/1,516,080 alleles · ultra-rare exomes 3/1,363,828 · genomes 6/152,252 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0142%	7,018
African / African-American	0.00142%	70,398
European (non-Finnish)	8.77e-05%	1,140,352

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.Pro44Gln
Coding: c.131C>A
MANE Select: NM_024306
dbSNP: rs915291720
Type: single nucleotide variant
Location: chr16:74774625 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.53
Residue 44: the cytochrome b5 heme-binding domain

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: neurodegeneration with brain iron accumulation

Similar variants

FA2H p.Pro44Ser Pathogenic/Likely pathogenic ★★ same residue
FA2H p.Pro44Thr Uncertain significance ★ ⚠ same residue
FA2H c.506+1G>C Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Arg269His Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Met1Val Pathogenic ★★ same condition
FA2H p.Pro148Leu Pathogenic/Likely pathogenic ★★ same condition
FA2H p.Pro44fs Pathogenic ★★ same residue
FA2H p.Arg269Cys Uncertain significance ★★ ⚠ 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-pro44gln (accessed [today's date]).

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