Is FLG p.Gln686Pro (c.2057A>C) pathogenic?

FLG p.Gln686Pro (c.2057A>C) is classified Uncertain significance in FLG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-02). AlphaMissense: likely benign (0.1165); Rare (popmax 0.117%, sas); Associated with Inborn genetic diseases.

What condition is associated with FLG p.Gln686Pro (c.2057A>C)?

FLG p.Gln686Pro (c.2057A>C) is associated with Inborn genetic diseases, ichthyosis vulgaris (ClinVar).

How common is FLG p.Gln686Pro (c.2057A>C) in the general population?

FLG p.Gln686Pro (c.2057A>C) is rare (popmax 0.117%, sas) (gnomAD).

What do computational predictors say about FLG p.Gln686Pro (c.2057A>C)?

AlphaMissense predicts likely benign (score 0.1165) — an in-silico prediction, not a clinical call.

FLG p.Gln686Pro

c.2057A>C · rs755034552 · VCV2361945

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1165 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.117%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1165	likely benign
REVEL	0.024	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 -1.3	GERP -0.2
Overall
CADD	11.04	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 0.117% South Asian · 107/91,072 alleles

Filtering AF 0.0994% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0927%

Overall 0.00688% 111/1,613,964 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.117%	851
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.00134%	74,864

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.Gln686Pro
Coding: c.2057A>C
MANE Select: NM_002016
dbSNP: rs755034552
Type: single nucleotide variant
Location: chr1:152312829 (GRCh38)
Gene constraint: LOEUF 1.932 · pLI <0.01 (gnomAD)
Residue 686: the 'disordered' region

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

Also linked: ichthyosis vulgaris

Similar variants

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FLG p.Ser2554Ter Pathogenic/Likely pathogenic ★★ same condition
FLG p.Ser3296Ter Pathogenic ★★ same condition
FLG p.Arg1133Gln Uncertain significance ★★ ⚠ same condition
FLG p.Gly2545Val Uncertain significance ★★ ⚠ same condition

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-gln686pro (accessed [today's date]).

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