Is FMN2 p.Ser76Thr (c.226T>A) pathogenic?

FMN2 p.Ser76Thr (c.226T>A) is classified Uncertain significance in FMN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-20). AlphaMissense: ambiguous (0.463); Very rare (popmax 0.00289%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FMN2 p.Ser76Thr (c.226T>A)?

FMN2 p.Ser76Thr (c.226T>A) is associated with Inborn genetic diseases (ClinVar).

How common is FMN2 p.Ser76Thr (c.226T>A) in the general population?

FMN2 p.Ser76Thr (c.226T>A) is very rare (popmax 0.00289%, nfe) (gnomAD).

What do computational predictors say about FMN2 p.Ser76Thr (c.226T>A)?

AlphaMissense predicts ambiguous (score 0.463) — an in-silico prediction, not a clinical call.

FMN2 p.Ser76Thr

c.226T>A · rs201857219 · VCV2360595

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.463 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00289%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.463	ambiguous
REVEL	0.072	moderately benign-leaning
SaProt	LLR -8.35	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 31 kb · p 0.15 · regional, not allelic
Overall
CADD	24.4	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 0.00289% European (non-Finnish) · 34/1,176,578 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00211% 34/1,608,368 alleles · very rare

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: FMN2
Protein: p.Ser76Thr
Coding: c.226T>A
MANE Select: NM_020066
dbSNP: rs201857219
Type: single nucleotide variant
Location: chr1:240092335 (GRCh38)
Gene constraint: LOEUF 0.51 · pLI 0.51 (gnomAD)
Structure: AlphaFold pLDDT 51.48 · 2 PDB
Residue 76: the 'disordered' region

Full FMN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FMN2 p.Ala367Val Uncertain significance ★★ ⚠ same condition
FMN2 p.Ala508Val Uncertain significance ★★ ⚠ same condition
FMN2 p.Asp352Tyr Uncertain significance ★★ ⚠ same condition
FMN2 p.Gly244Ala Uncertain significance ★★ ⚠ same condition
FMN2 p.Gly553Arg Uncertain significance ★★ ⚠ same condition
FMN2 p.Lys1681Arg Uncertain significance ★★ ⚠ same condition
FMN2 p.Pro1221Ser Uncertain significance ★★ ⚠ same condition
FMN2 p.Pro1228Leu 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/fmn2-p-ser76thr (accessed [today's date]).

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