Is FLG2 p.Ser673Pro (c.2017T>C) pathogenic?

FLG2 p.Ser673Pro (c.2017T>C) is classified Uncertain significance in FLG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely benign (0.2115); Very rare (popmax 0.00333%, amr).

How common is FLG2 p.Ser673Pro (c.2017T>C) in the general population?

FLG2 p.Ser673Pro (c.2017T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about FLG2 p.Ser673Pro (c.2017T>C)?

AlphaMissense predicts likely benign (score 0.2115) — an in-silico prediction, not a clinical call.

FLG2 p.Ser673Pro

c.2017T>C · VCV4668855

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2115 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

⚠ 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	0.2115	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -10.09	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.9	GERP 1.2
Regional constraint	o/e 0.96	unconstrained · MANE · 8,271 bp · p 0.039 · regional, not allelic
Overall
CADD	12.51	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,974 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,613,426 alleles · very rare exomes 2/1,461,868 · genomes 0/151,558 · joint denominator

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: FLG2
Protein: p.Ser673Pro
Coding: c.2017T>C
MANE Select: NM_001014342
Type: single nucleotide variant
Location: chr1:152355769 (GRCh38)

Full FLG2 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/flg2-p-ser673pro (accessed [today's date]).

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