Is FREM2 p.Arg488Gln (c.1463G>A) pathogenic?

FREM2 p.Arg488Gln (c.1463G>A) is classified Uncertain significance in FREM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-17). AlphaMissense: likely benign (0.0692); Ultra-rare (popmax 0.012%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FREM2 p.Arg488Gln (c.1463G>A)?

FREM2 p.Arg488Gln (c.1463G>A) is associated with Inborn genetic diseases, isolated cryptophthalmia, Fraser syndrome 2 (ClinVar).

How common is FREM2 p.Arg488Gln (c.1463G>A) in the general population?

FREM2 p.Arg488Gln (c.1463G>A) is ultra-rare (popmax 0.012%, nfe) (gnomAD).

What do computational predictors say about FREM2 p.Arg488Gln (c.1463G>A)?

AlphaMissense predicts likely benign (score 0.0692) — an in-silico prediction, not a clinical call.

FREM2 p.Arg488Gln

c.1463G>A · rs146258429 · VCV2066795

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0692 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0692	likely benign
REVEL	0.08	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 3.4	GERP 0.62, phastCons 0.75
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	20.4	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 0.012% European (non-Finnish) · 142/1,180,032 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0098%

Overall 0.00991% 160/1,613,830 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.012%	8,310
African / African-American	0.012%	8,322
Remaining individualsnot grpmax-eligible	0.0096%	10,413
East Asian	0.00223%	44,876
South Asian	0.0022%	45,537

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.Arg488Gln
Coding: c.1463G>A
MANE Select: NM_207361
dbSNP: rs146258429
Type: single nucleotide variant
Location: chr13:38688807 (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

Also linked: isolated cryptophthalmia Fraser syndrome 2

Similar variants

FREM2 p.Arg488Leu Uncertain significance ★ ⚠ same residue
FREM2 p.Arg488= 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-arg488gln (accessed [today's date]).

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