Is FREM2 p.Gly2139Asp (c.6416G>A) pathogenic?

FREM2 p.Gly2139Asp (c.6416G>A) is classified Uncertain significance in FREM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.2786); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with FREM2 p.Gly2139Asp (c.6416G>A)?

FREM2 p.Gly2139Asp (c.6416G>A) is associated with Inborn genetic diseases (ClinVar).

How common is FREM2 p.Gly2139Asp (c.6416G>A) in the general population?

FREM2 p.Gly2139Asp (c.6416G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about FREM2 p.Gly2139Asp (c.6416G>A)?

AlphaMissense predicts likely benign (score 0.2786) — an in-silico prediction, not a clinical call.

FREM2 p.Gly2139Asp

c.6416G>A · rs371458568 · VCV2120370

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2786 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2786	likely benign
REVEL	0.184	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	18.83	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,014 alleles

Overall 0.000137% 2/1,461,686 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,014
European (non-Finnish)	8.48e-05%	1,179,888

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: FREM2
Protein: p.Gly2139Asp
Coding: c.6416G>A
MANE Select: NM_207361
dbSNP: rs371458568
Type: single nucleotide variant
Location: chr13:38850074 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 2139: the calx-beta 4 domain; a UniProt-annotated variant site (in cryptop)

Full FREM2 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

Similar variants

FREM2 p.Gly2139Val Uncertain significance ★★ ⚠ same residue
FREM2 p.Gly2139= Likely benign ★ same residue
FREM2 p.Ala1029Val Uncertain significance ★★ ⚠ same condition
FREM2 p.Ala565Gly Uncertain significance ★★ same condition
FREM2 p.Ala61Pro Uncertain significance ★★ ⚠ same condition
FREM2 p.Arg1166Cys Uncertain significance ★★ ⚠ same condition
FREM2 p.Arg1523Cys Uncertain significance ★★ same condition
FREM2 p.Arg156Leu 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/frem2-p-gly2139asp (accessed [today's date]).

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