Is FREM2 p.Asp2006Val (c.6017A>T) pathogenic?

FREM2 p.Asp2006Val (c.6017A>T) is classified Uncertain significance in FREM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-01). AlphaMissense: likely pathogenic (0.9118); Very rare (popmax 0.00263%, nfe); Associated with FREM2-related disorder.

What condition is associated with FREM2 p.Asp2006Val (c.6017A>T)?

FREM2 p.Asp2006Val (c.6017A>T) is associated with FREM2-related disorder (ClinVar).

How common is FREM2 p.Asp2006Val (c.6017A>T) in the general population?

FREM2 p.Asp2006Val (c.6017A>T) is very rare (popmax 0.00263%, nfe) (gnomAD).

What do computational predictors say about FREM2 p.Asp2006Val (c.6017A>T)?

AlphaMissense predicts likely pathogenic (score 0.9118) — an in-silico prediction, not a clinical call.

FREM2 p.Asp2006Val

c.6017A>T · rs763903628 · VCV3764609

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9118 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00263%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FREM2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9118	likely pathogenic · top 8% in FREM2
REVEL	0.694	pathogenic-leaning
SaProt	LLR -9.97	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	26.2	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 0.00263% European (non-Finnish) · 31/1,180,010 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00198% 32/1,613,996 alleles · very rare exomes 30/1,461,740 · genomes 2/152,256 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00263%	38,065
African / African-American	0.00133%	74,950

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.Asp2006Val
Coding: c.6017A>T
MANE Select: NM_207361
dbSNP: rs763903628
Type: single nucleotide variant
Location: chr13:38784806 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 2006: the calx-beta 3 domain; a UniProt-annotated variant site (in cryptop)

Full FREM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

FREM2-related disorder

Similar variants

FREM2 p.Asp2006His Uncertain significance ★★ same residue
FREM2 p.Asp2006Ala Uncertain significance ★ same residue
FREM2 c.6925+1G>T Likely pathogenic ★★ same condition
FREM2 p.Asn1048Ser Uncertain significance ★★ ⚠ same condition
FREM2 p.Gly811Glu Uncertain significance ★★ same condition
FREM2 p.Ile1460Val Uncertain significance ★★ ⚠ same condition
FREM2 p.Ile2952Thr Uncertain significance ★★ same condition
FREM2 p.Pro128Leu 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-asp2006val (accessed [today's date]).

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