Is FREM2 p.Pro362Leu (c.1085C>T) pathogenic?

FREM2 p.Pro362Leu (c.1085C>T) is classified Uncertain significance in FREM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-17). AlphaMissense: likely benign (0.0949); Very rare (popmax 0.00891%, eas); Associated with Inborn genetic diseases.

What condition is associated with FREM2 p.Pro362Leu (c.1085C>T)?

FREM2 p.Pro362Leu (c.1085C>T) is associated with Inborn genetic diseases, isolated cryptophthalmia, Fraser syndrome 2 (ClinVar).

How common is FREM2 p.Pro362Leu (c.1085C>T) in the general population?

FREM2 p.Pro362Leu (c.1085C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about FREM2 p.Pro362Leu (c.1085C>T)?

AlphaMissense predicts likely benign (score 0.0949) — an in-silico prediction, not a clinical call.

FREM2 p.Pro362Leu

c.1085C>T · rs761048192 · VCV3096777

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0949 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0949	likely benign
REVEL	0.193	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 2.7	GERP 1.7, phastCons 0.12
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	21.4	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 0.00891% East Asian · 4/44,872 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00031% 5/1,613,828 alleles · very rare exomes 4/1,461,632 · genomes 1/152,196 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,218
European (non-Finnish)	8.48e-05%	1,179,926

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.Pro362Leu
Coding: c.1085C>T
MANE Select: NM_207361
dbSNP: rs761048192
Type: single nucleotide variant
Location: chr13:38688429 (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.Pro362= 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
FREM2 p.Ala1029Val 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-pro362leu (accessed [today's date]).

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