Is FREM2 p.Pro318= (c.954C>G) pathogenic?

FREM2 p.Pro318= (c.954C>G) is classified Benign in FREM2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 14.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Pro318= (c.954C>G)?

FREM2 p.Pro318= (c.954C>G) is associated with Fraser syndrome 2 (ClinVar).

FREM2 p.Pro318=

Q: How common is FREM2 p.Pro318= (c.954C>G) in the general population?

FREM2 p.Pro318= (c.954C>G) is common (popmax 14.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.954C>G · rs9576597 · VCV311943

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 14.7%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Fraser syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.098	GERP -1.6, phastCons 0.92
Overall
CADD	9.042	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 14.7% East Asian · 6,610/44,854 alleles

Filtering AF 14.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.3%

Overall 1.27% 20,487/1,614,132 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	14.7%	7
South Asian	4.54%	22
Finnishnot grpmax-eligible	3.92%	25
Remaining individualsnot grpmax-eligible	1.96%	51
Middle Eastern	1.48%	67
African / African-American	1.23%	81
Ashkenazi Jewishnot grpmax-eligible	1.09%	92
Admixed American	0.671%	149
European (non-Finnish)	0.362%	277

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.Pro318=
Coding: c.954C>G
MANE Select: NM_207361
dbSNP: rs9576597
Type: single nucleotide variant
Location: chr13:38688298 (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

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

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-pro318 (accessed [today's date]).

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