Is FLG p.Ser3558Pro (c.10672T>C) pathogenic?

FLG p.Ser3558Pro (c.10672T>C) is classified Benign in FLG (ClinVar, No assertion criteria, 2 submitters). AlphaMissense: likely benign (0.2112); Low-frequency (popmax 2.48%, sas).

How common is FLG p.Ser3558Pro (c.10672T>C) in the general population?

FLG p.Ser3558Pro (c.10672T>C) is low-frequency (popmax 2.48%, sas) (gnomAD).

What do computational predictors say about FLG p.Ser3558Pro (c.10672T>C)?

AlphaMissense predicts likely benign (score 0.2112) — an in-silico prediction, not a clinical call.

FLG p.Ser3558Pro

c.10672T>C · rs185760814 · VCV1297565

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2112 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.48%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.2112	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.17	GERP -2.2
Overall
CADD	17.25	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 2.48% South Asian · 2,233/90,194 alleles

Filtering AF 2.39% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.36%

Overall 0.151% 2,430/1,611,154 alleles · low-frequency exomes 2,361/1,461,188 · genomes 69/149,966 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	2.48%	40
East Asian	0.153%	655
Middle Eastern	0.132%	757
Remaining individualsnot grpmax-eligible	0.111%	905
African / African-American	0.00404%	24,779
European (non-Finnish)	0.00398%	25,098
Admixed American	0.00335%	29,811

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.Ser3558Pro
Coding: c.10672T>C
MANE Select: NM_002016
dbSNP: rs185760814
Type: single nucleotide variant
Location: chr1:152304214 (GRCh38)
Gene constraint: LOEUF 1.932 · pLI <0.01 (gnomAD)
Residue 3558: the 'disordered' region

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

Similar variants

FLG p.Arg1798Ter Pathogenic/Likely pathogenic ★★ same type
FLG p.Gln1790Ter Pathogenic ★★ same type
FLG p.Gln355Ter Pathogenic ★★ same type
FLG p.Ser2080Ter Pathogenic ★★ same type
FLG p.Ser2554Ter Pathogenic/Likely pathogenic ★★ same type
FLG p.Ser3296Ter Pathogenic ★★ same type
FLG p.Arg1133Gln Uncertain significance ★★ ⚠ same type
FLG p.Gln686Pro Uncertain significance ★★ ⚠ same type

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-ser3558pro (accessed [today's date]).

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