Is FREM2 p.Ser2123Pro (c.6367T>C) pathogenic?

FREM2 p.Ser2123Pro (c.6367T>C) is classified Uncertain significance in FREM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-13). AlphaMissense: likely pathogenic (0.6935); Ultra-rare (popmax 0.0201%, eas); Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Ser2123Pro (c.6367T>C)?

FREM2 p.Ser2123Pro (c.6367T>C) is associated with Fraser syndrome 2, isolated cryptophthalmia (ClinVar).

How common is FREM2 p.Ser2123Pro (c.6367T>C) in the general population?

FREM2 p.Ser2123Pro (c.6367T>C) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about FREM2 p.Ser2123Pro (c.6367T>C)?

AlphaMissense predicts likely pathogenic (score 0.6935) — an in-silico prediction, not a clinical call.

FREM2 p.Ser2123Pro

c.6367T>C · rs116453495 · VCV883515

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6935 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

Fraser syndrome 2

Computational evidence

Protein change
AlphaMissense	0.6935	likely pathogenic
REVEL	0.259	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -1.3, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	22.0	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 0.0201% East Asian · 9/44,852 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0078%

Overall 0.00112% 18/1,610,860 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,984
Remaining individualsnot grpmax-eligible	0.0128%	7,799
European (non-Finnish)	8.49e-05%	1,177,210

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.Ser2123Pro
Coding: c.6367T>C
MANE Select: NM_207361
dbSNP: rs116453495
Type: single nucleotide variant
Location: chr13:38848658 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 2123: the calx-beta 4 domain; 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-ser2123pro (accessed [today's date]).

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