Is FLG p.Arg412= (c.1236T>C) pathogenic?

FLG p.Arg412= (c.1236T>C) is classified Benign in FLG (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-11-26). Common (popmax 20.7%, sas) — too common for a highly-penetrant pathogenic allele.

FLG p.Arg412=

Q: How common is FLG p.Arg412= (c.1236T>C) in the general population?

FLG p.Arg412= (c.1236T>C) is common (popmax 20.7%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1236T>C · rs11582620 · VCV1259919

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 20.7%, sas) — too common for a highly-penetrant pathogenic allele

⚠ 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
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -2.1	GERP -3.3
Overall
CADD	2.093	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 20.7% South Asian · 18,860/91,018 alleles

Filtering AF 20.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 20.4%

Overall 11.9% 192,707/1,613,394 alleles · common exomes 178,877/1,461,886 · genomes 13,830/151,508 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	20.7%	5
Amishnot grpmax-eligible	14.4%	7
Finnishnot grpmax-eligible	12.9%	8
European (non-Finnish)	12.2%	8
East Asian	11.6%	9
Remaining individualsnot grpmax-eligible	11%	9
Middle Eastern	9.84%	10
Admixed American	8.66%	12
Ashkenazi Jewishnot grpmax-eligible	6.55%	15
African / African-American	1.89%	53

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.Arg412=
Coding: c.1236T>C
MANE Select: NM_002016
dbSNP: rs11582620
Type: single nucleotide variant
Location: chr1:152313650 (GRCh38)

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

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-arg412 (accessed [today's date]).

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