Is FREM2 p.Pro2837Ser (c.8509C>T) pathogenic?

FREM2 p.Pro2837Ser (c.8509C>T) is classified Conflicting classifications of pathogenicity in FREM2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-30). AlphaMissense: likely benign (0.1291); Very rare (popmax 0.00167%, amr); Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Pro2837Ser (c.8509C>T)?

FREM2 p.Pro2837Ser (c.8509C>T) is associated with Fraser syndrome 2, isolated cryptophthalmia (ClinVar).

How common is FREM2 p.Pro2837Ser (c.8509C>T) in the general population?

FREM2 p.Pro2837Ser (c.8509C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about FREM2 p.Pro2837Ser (c.8509C>T)?

AlphaMissense predicts likely benign (score 0.1291) — an in-silico prediction, not a clinical call.

FREM2 p.Pro2837Ser

c.8509C>T · rs766715445 · VCV312031

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1291 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Fraser syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1291	likely benign
REVEL	0.327	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 25 kb · p 0.00037 · regional, not allelic
Overall
CADD	22.2	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 0.00167% Admixed American · 1/59,992 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00508% 82/1,613,808 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.216%	463
Remaining individualsnot grpmax-eligible	0.0112%	8,925
Admixed Americangrpmax	0.00167%	59,992
African / African-American	0.00134%	74,866
European (non-Finnish)	0.000763%	131,101

Ashkenazi Jewish 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.Pro2837Ser
Coding: c.8509C>T
MANE Select: NM_207361
dbSNP: rs766715445
Type: single nucleotide variant
Location: chr13:38876347 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 2837: a UniProt-annotated variant site (in cryptop)

Full FREM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Fraser syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: isolated cryptophthalmia

Similar variants

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.Ala1659Thr Uncertain significance ★★ ⚠ same condition
FREM2 p.Ala1664Val 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-pro2837ser (accessed [today's date]).

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