Is FLG p.Ser3441Arg (c.10323C>G) pathogenic?

FLG p.Ser3441Arg (c.10323C>G) is classified Uncertain significance in FLG (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: likely benign (0.302); Ultra-rare (popmax 0.0537%, amr); Associated with Inborn genetic diseases.

What condition is associated with FLG p.Ser3441Arg (c.10323C>G)?

FLG p.Ser3441Arg (c.10323C>G) is associated with Inborn genetic diseases (ClinVar).

How common is FLG p.Ser3441Arg (c.10323C>G) in the general population?

FLG p.Ser3441Arg (c.10323C>G) is ultra-rare (popmax 0.0537%, amr) (gnomAD).

What do computational predictors say about FLG p.Ser3441Arg (c.10323C>G)?

AlphaMissense predicts likely benign (score 0.302) — an in-silico prediction, not a clinical call.

FLG p.Ser3441Arg

c.10323C>G · rs944486525 · VCV2349140

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.302 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0537%, amr)

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	0.302	likely benign
REVEL	0.057	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 -1.6	GERP 0.6
Regional constraint	o/e 1.38	unconstrained · MANE · 2,903 bp · p 2.8e-40 · regional, not allelic
Overall
CADD	7.774	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 0.0537% Admixed American · 32/59,606 alleles

Filtering AF 0.039% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0341%

Overall 0.00603% 97/1,609,438 alleles · ultra-rare exomes 69/1,458,848 · genomes 28/150,590 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0537%	1,863
Remaining individualsnot grpmax-eligible	0.00802%	12,468
African / African-American	0.00672%	14,887
European (non-Finnish)	0.00467%	21,412

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.Ser3441Arg
Coding: c.10323C>G
MANE Select: NM_002016
dbSNP: rs944486525
Type: single nucleotide variant
Location: chr1:152304563 (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-ser3441arg (accessed [today's date]).

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