Is FLG p.Arg3530Ser (c.10590G>T) pathogenic?

FLG p.Arg3530Ser (c.10590G>T) is classified Benign in FLG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-09). AlphaMissense: likely benign (0.2323); Common (popmax 50.7%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about FLG p.Arg3530Ser (c.10590G>T)?

AlphaMissense predicts likely benign (score 0.2323) — an in-silico prediction, not a clinical call.

FLG p.Arg3530Ser

Q: How common is FLG p.Arg3530Ser (c.10590G>T) in the general population?

FLG p.Arg3530Ser (c.10590G>T) is common (popmax 50.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.10590G>T · rs72697000 · VCV1237029

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2323 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 50.7%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

⚠ 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	0.2323	likely benign
REVEL	0.06	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 -20	GERP -3
Regional constraint	o/e 1.38	unconstrained · MANE · 2,903 bp · p 2.8e-40 · regional, not allelic
Overall
CADD	3.231	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 50.7% East Asian · 22,295/43,998 alleles

Filtering AF 50.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 49.9%

Overall 16.8% 269,582/1,608,444 alleles · common exomes 247,744/1,458,596 · genomes 21,838/149,848 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	50.7%	2
Admixed American	37.4%	3
South Asian	34.9%	3
Ashkenazi Jewishnot grpmax-eligible	27%	4
Middle Eastern	24.2%	4
Remaining individualsnot grpmax-eligible	20%	5
Finnishnot grpmax-eligible	16.5%	6
Amishnot grpmax-eligible	15.6%	6
European (non-Finnish)	13.5%	7
African / African-American	3.01%	33

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.Arg3530Ser
Coding: c.10590G>T
MANE Select: NM_002016
dbSNP: rs72697000
Type: single nucleotide variant
Location: chr1:152304296 (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-arg3530ser (accessed [today's date]).

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