Is FREM2 p.Arg710His (c.2129G>A) pathogenic?

FREM2 p.Arg710His (c.2129G>A) is classified Conflicting classifications of pathogenicity in FREM2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-25). AlphaMissense: likely benign (0.0732); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with FREM2 p.Arg710His (c.2129G>A)?

FREM2 p.Arg710His (c.2129G>A) is associated with Inborn genetic diseases, isolated cryptophthalmia, Fraser syndrome 2 (ClinVar).

How common is FREM2 p.Arg710His (c.2129G>A) in the general population?

FREM2 p.Arg710His (c.2129G>A) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about FREM2 p.Arg710His (c.2129G>A)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

FREM2 p.Arg710His

c.2129G>A · rs372166899 · VCV2356643

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.093	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 0.66, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	22.5	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 0.0107% African / African-American · 8/74,902 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000867% 14/1,613,926 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,363
East Asian	0.00223%	44,876
European (non-Finnish)	0.000424%	236,003

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.Arg710His
Coding: c.2129G>A
MANE Select: NM_207361
dbSNP: rs372166899
Type: single nucleotide variant
Location: chr13:38689473 (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.Arg710Cys 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-arg710his (accessed [today's date]).

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