Is FREM2 p.Asp331Glu (c.993C>G) pathogenic?

FREM2 p.Asp331Glu (c.993C>G) is classified Uncertain significance in FREM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-01). AlphaMissense: ambiguous (0.4125); Very rare (popmax 0.00144%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FREM2 p.Asp331Glu (c.993C>G)?

FREM2 p.Asp331Glu (c.993C>G) is associated with Inborn genetic diseases (ClinVar).

How common is FREM2 p.Asp331Glu (c.993C>G) in the general population?

FREM2 p.Asp331Glu (c.993C>G) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about FREM2 p.Asp331Glu (c.993C>G)?

AlphaMissense predicts ambiguous (score 0.4125) — an in-silico prediction, not a clinical call.

FREM2 p.Asp331Glu

c.993C>G · rs767767229 · VCV1378103

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4125 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4125	ambiguous
REVEL	0.134	moderately benign-leaning
SaProt	LLR -6.11	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.23	GERP -4, phastCons 0.97
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	16.32	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 0.00144% European (non-Finnish) · 17/1,180,028 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00118% 19/1,614,204 alleles · very rare exomes 19/1,461,884 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,256
European (non-Finnish)grpmax	0.00144%	69,414

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp331Glu
Coding: c.993C>G
MANE Select: NM_207361
dbSNP: rs767767229
Type: single nucleotide variant
Location: chr13:38688337 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)

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-asp331glu (accessed [today's date]).

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