Is FREM2 p.Pro2002Ser (c.6004C>T) pathogenic?

FREM2 p.Pro2002Ser (c.6004C>T) is classified Uncertain significance in FREM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-29). AlphaMissense: likely benign (0.1186); Ultra-rare (popmax 0.0268%, eas); Associated with Inborn genetic diseases.

What condition is associated with FREM2 p.Pro2002Ser (c.6004C>T)?

FREM2 p.Pro2002Ser (c.6004C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FREM2 p.Pro2002Ser (c.6004C>T) in the general population?

FREM2 p.Pro2002Ser (c.6004C>T) is ultra-rare (popmax 0.0268%, eas) (gnomAD).

What do computational predictors say about FREM2 p.Pro2002Ser (c.6004C>T)?

AlphaMissense predicts likely benign (score 0.1186) — an in-silico prediction, not a clinical call.

FREM2 p.Pro2002Ser

c.6004C>T · rs372782469 · VCV288263

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1186 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0268%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1186	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -3.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.9	GERP -0.74, phastCons 0.91
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	15.67	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 0.0268% East Asian · 12/44,852 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00112% 18/1,614,114 alleles · ultra-rare exomes 10/1,461,812 · genomes 8/152,302 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0268%	3,738
African / African-American	0.00533%	18,762
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	8.47e-05%	1,180,004

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.Pro2002Ser
Coding: c.6004C>T
MANE Select: NM_207361
dbSNP: rs372782469
Type: single nucleotide variant
Location: chr13:38784793 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 2002: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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
FREM2 p.Arg1765Cys Uncertain significance ★★ ⚠ same condition
FREM2 p.Arg1765His 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-pro2002ser (accessed [today's date]).

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