Is FREM2 p.Phe1070Ser (c.3209T>C) pathogenic?

FREM2 p.Phe1070Ser (c.3209T>C) is classified Benign/Likely benign in FREM2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0497); Common (popmax 75.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Phe1070Ser (c.3209T>C)?

FREM2 p.Phe1070Ser (c.3209T>C) is associated with Fraser syndrome 2, isolated cryptophthalmia, Fraser syndrome 1 (ClinVar).

What do computational predictors say about FREM2 p.Phe1070Ser (c.3209T>C)?

AlphaMissense predicts likely benign (score 0.0497) — an in-silico prediction, not a clinical call.

FREM2 p.Phe1070Ser

Q: How common is FREM2 p.Phe1070Ser (c.3209T>C) in the general population?

FREM2 p.Phe1070Ser (c.3209T>C) is common (popmax 75.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3209T>C · rs2496425 · VCV193525

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0497 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 75.7%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Fraser syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0497	likely benign
REVEL	0.097	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 3.3	GERP -0.28, phastCons 0.95
Regional constraint	o/e 1.05	unconstrained · MANE · 169 kb · p 0.0054 · regional, not allelic
Overall
CADD	14.59	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 75.7% African / African-American · 56,776/74,966 alleles

Filtering AF 75.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 75%

Overall 30.3% 489,753/1,613,692 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	75.7%	1
Admixed American	42.8%	2
East Asian	38.8%	3
Remaining individualsnot grpmax-eligible	32%	3
Finnishnot grpmax-eligible	31.6%	3
Ashkenazi Jewishnot grpmax-eligible	31.4%	3
South Asian	29.5%	3
Middle Eastern	27.5%	4
Amishnot grpmax-eligible	27.2%	4
European (non-Finnish)	26.4%	4

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.Phe1070Ser
Coding: c.3209T>C
MANE Select: NM_207361
dbSNP: rs2496425
Type: single nucleotide variant
Location: chr13:38690553 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 1070: a UniProt-annotated variant site (in cryptop); a UniProt-annotated variant site (in)

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 Fraser syndrome 1

Similar variants

FREM2 p.Arg1355Ter Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.Arg2243Ter 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-phe1070ser (accessed [today's date]).

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