Is FLG p.Ser535Pro (c.1603T>C) pathogenic?

FLG p.Ser535Pro (c.1603T>C) is classified Likely benign in FLG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-05). AlphaMissense: likely benign (0.1301); Low-frequency (popmax 3.99%, afr).

How common is FLG p.Ser535Pro (c.1603T>C) in the general population?

FLG p.Ser535Pro (c.1603T>C) is low-frequency (popmax 3.99%, afr) (gnomAD).

What do computational predictors say about FLG p.Ser535Pro (c.1603T>C)?

AlphaMissense predicts likely benign (score 0.1301) — an in-silico prediction, not a clinical call.

FLG p.Ser535Pro

c.1603T>C · rs74129464 · VCV1220490

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1301 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.99%, afr)

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	0.1301	likely benign
REVEL	0.088	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 -4.6	GERP -2.3
Regional constraint	o/e 1.77	unconstrained · MANE · 8,404 bp · p 0 · regional, not allelic
Overall
CADD	10.57	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 3.99% African / African-American · 2,976/74,644 alleles

Filtering AF 3.87% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.82%

Overall 0.238% 3,843/1,613,388 alleles · low-frequency exomes 2,116/1,461,866 · genomes 1,727/151,522 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.99%	25
Middle Eastern	0.545%	184
Remaining individualsnot grpmax-eligible	0.325%	308
Admixed American	0.282%	355
Ashkenazi Jewishnot grpmax-eligible	0.105%	955
European (non-Finnish)	0.034%	2,942
South Asian	0.033%	3,034

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.Ser535Pro
Coding: c.1603T>C
MANE Select: NM_002016
dbSNP: rs74129464
Type: single nucleotide variant
Location: chr1:152313283 (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-ser535pro (accessed [today's date]).

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