Is FLG p.Arg415Trp (c.1243C>T) pathogenic?

FLG p.Arg415Trp (c.1243C>T) is classified Uncertain significance in FLG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0978); Ultra-rare (popmax 0.02%, amr); Associated with Inborn genetic diseases.

What condition is associated with FLG p.Arg415Trp (c.1243C>T)?

FLG p.Arg415Trp (c.1243C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FLG p.Arg415Trp (c.1243C>T) in the general population?

FLG p.Arg415Trp (c.1243C>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about FLG p.Arg415Trp (c.1243C>T)?

AlphaMissense predicts likely benign (score 0.0978) — an in-silico prediction, not a clinical call.

FLG p.Arg415Trp

c.1243C>T · VCV4829113

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0978 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0978	likely benign
REVEL	0.01	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 -3.1	GERP -3.3
Overall
CADD	4.589	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% Admixed American · 12/59,888 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.009%

Overall 0.0036% 58/1,612,772 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	4,991
Middle Eastern	0.0165%	6,068
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,802
East Asian	0.00447%	22,352
Remaining individualsnot grpmax-eligible	0.0032%	31,224
European (non-Finnish)	0.00314%	31,886
African / African-American	0.00134%	74,466
South Asian	0.0011%	90,994

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.Arg415Trp
Coding: c.1243C>T
Type: single nucleotide variant
Location: chr1:152313643 (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-arg415trp (accessed [today's date]).

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