Is FREM2 p.Arg710Cys (c.2128C>T) pathogenic?

FREM2 p.Arg710Cys (c.2128C>T) is classified Likely benign in FREM2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1141); Rare (popmax 0.415%, nfe); Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Arg710Cys (c.2128C>T)?

FREM2 p.Arg710Cys (c.2128C>T) is associated with Fraser syndrome 2 (ClinVar).

How common is FREM2 p.Arg710Cys (c.2128C>T) in the general population?

FREM2 p.Arg710Cys (c.2128C>T) is rare (popmax 0.415%, nfe) (gnomAD).

What do computational predictors say about FREM2 p.Arg710Cys (c.2128C>T)?

AlphaMissense predicts likely benign (score 0.1141) — an in-silico prediction, not a clinical call.

FREM2 p.Arg710Cys

c.2128C>T · rs41292753 · VCV193532

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1141 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.415%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Fraser syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1141	likely benign
REVEL	0.179	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 1.8	GERP 2.6, phastCons 0.92
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.415% European (non-Finnish) · 4,891/1,179,966 alleles

Filtering AF 0.405% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.401%

Overall 0.336% 5,431/1,614,018 alleles · rare exomes 5,028/1,461,806 · genomes 403/152,212 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.415%	241
Remaining individualsnot grpmax-eligible	0.299%	334
Admixed American	0.262%	382
Finnishnot grpmax-eligible	0.161%	621
Amishnot grpmax-eligible	0.11%	912
Ashkenazi Jewishnot grpmax-eligible	0.108%	925
African / African-American	0.0693%	1,443
Middle Eastern	0.0495%	2,021
South Asian	0.00439%	22,770
East Asian	0.00223%	44,862

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.Arg710Cys
Coding: c.2128C>T
MANE Select: NM_207361
dbSNP: rs41292753
Type: single nucleotide variant
Location: chr13:38689472 (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.Arg710His Conflicting classifications of pathogenicity ★ ⚠ 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.Ala1659Thr 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-arg710cys (accessed [today's date]).

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