Is FLG p.Trp3333Arg (c.9997T>C) pathogenic?

FLG p.Trp3333Arg (c.9997T>C) is classified Likely benign in FLG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-08). AlphaMissense: likely benign (0.0825); Very rare (popmax 0.0061%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FLG p.Trp3333Arg (c.9997T>C)?

FLG p.Trp3333Arg (c.9997T>C) is associated with Inborn genetic diseases (ClinVar).

How common is FLG p.Trp3333Arg (c.9997T>C) in the general population?

FLG p.Trp3333Arg (c.9997T>C) is very rare (popmax 0.0061%, nfe) (gnomAD).

What do computational predictors say about FLG p.Trp3333Arg (c.9997T>C)?

AlphaMissense predicts likely benign (score 0.0825) — an in-silico prediction, not a clinical call.

FLG p.Trp3333Arg

c.9997T>C · VCV3279073

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0825 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0061%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0825	likely benign
REVEL	0.006	strongly benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -6.3	GERP -3.3
Overall
CADD	0.006	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0061% European (non-Finnish) · 72/1,179,814 alleles

Filtering AF 0.00495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00455%

Overall 0.00502% 81/1,613,446 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0061%	16,386
South Asian	0.0055%	18,196
Admixed American	0.005%	19,983
Remaining individualsnot grpmax-eligible	0.0016%	62,494

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: FLG
Protein: p.Trp3333Arg
Coding: c.9997T>C
Type: single nucleotide variant
Location: chr1:152304889 (GRCh38)

Full FLG 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

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/flg-p-trp3333arg (accessed [today's date]).

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