Is FLG p.Val409Ala (c.1226T>C) pathogenic?

FLG p.Val409Ala (c.1226T>C) is classified Uncertain significance in FLG (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-30). AlphaMissense: likely benign (0.1417); Ultra-rare (popmax 0.033%, sas); Associated with Inborn genetic diseases.

What condition is associated with FLG p.Val409Ala (c.1226T>C)?

FLG p.Val409Ala (c.1226T>C) is associated with Inborn genetic diseases (ClinVar).

How common is FLG p.Val409Ala (c.1226T>C) in the general population?

FLG p.Val409Ala (c.1226T>C) is ultra-rare (popmax 0.033%, sas) (gnomAD).

What do computational predictors say about FLG p.Val409Ala (c.1226T>C)?

AlphaMissense predicts likely benign (score 0.1417) — an in-silico prediction, not a clinical call.

FLG p.Val409Ala

c.1226T>C · rs368161602 · VCV2362280

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1417 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.1417	likely benign
REVEL	0.078	moderately 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 -0.75	GERP -3.2
Regional constraint	o/e 1.77	unconstrained · MANE · 8,404 bp · p 0 · regional, not allelic
Overall
CADD	7.194	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 0.033% South Asian · 30/91,046 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.00688% 111/1,613,564 alleles · ultra-rare exomes 104/1,461,876 · genomes 7/151,688 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.033%	3,035
European (non-Finnish)	0.00661%	15,127
Remaining individualsnot grpmax-eligible	0.0032%	31,238
Finnishnot grpmax-eligible	0.00156%	63,978

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.Val409Ala
Coding: c.1226T>C
MANE Select: NM_002016
dbSNP: rs368161602
Type: single nucleotide variant
Location: chr1:152313660 (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-val409ala (accessed [today's date]).

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