Is FREM2 p.Arg480Trp (c.1438C>T) pathogenic?

FREM2 p.Arg480Trp (c.1438C>T) is classified Uncertain significance in FREM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-22). AlphaMissense: likely benign (0.0845); Ultra-rare (popmax 0.0164%, mid); Associated with isolated cryptophthalmia.

What condition is associated with FREM2 p.Arg480Trp (c.1438C>T)?

FREM2 p.Arg480Trp (c.1438C>T) is associated with isolated cryptophthalmia, Fraser syndrome 2 (ClinVar).

How common is FREM2 p.Arg480Trp (c.1438C>T) in the general population?

FREM2 p.Arg480Trp (c.1438C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about FREM2 p.Arg480Trp (c.1438C>T)?

AlphaMissense predicts likely benign (score 0.0845) — an in-silico prediction, not a clinical call.

FREM2 p.Arg480Trp

c.1438C>T · rs756426681 · VCV2371352

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0845 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

isolated cryptophthalmia

Computational evidence

Protein change
AlphaMissense	0.0845	likely benign
REVEL	0.074	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 0.37	GERP -5.4, phastCons 0.012
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	19.79	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00511% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00496% 80/1,613,886 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00627%	15,946
African / African-American	0.00401%	24,968
Remaining individualsnot grpmax-eligible	0.0016%	62,484
Finnishnot grpmax-eligible	0.00156%	63,898

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.Arg480Trp
Coding: c.1438C>T
MANE Select: NM_207361
dbSNP: rs756426681
Type: single nucleotide variant
Location: chr13:38688782 (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

isolated cryptophthalmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Fraser syndrome 2

Similar variants

FREM2 p.Arg480Gln Uncertain significance ★ ⚠ same residue
FREM2 p.Arg480= Likely benign ★ same residue
FREM2 p.Arg1355Ter Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.Arg638Ter Likely pathogenic ★★ same condition
FREM2 p.Arg736Ter Pathogenic ★★ same condition
FREM2 p.Arg809Ter Pathogenic ★★ same condition
FREM2 p.Gln1051Ter Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.Gln717Ter Likely pathogenic ★★ 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-arg480trp (accessed [today's date]).

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