Is CYFIP2 p.Pro738Ser (c.2212C>T) pathogenic?

CYFIP2 p.Pro738Ser (c.2212C>T) is classified Uncertain significance in CYFIP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-02). AlphaMissense: likely benign (0.1947); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with CYFIP2 p.Pro738Ser (c.2212C>T)?

CYFIP2 p.Pro738Ser (c.2212C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CYFIP2 p.Pro738Ser (c.2212C>T) in the general population?

CYFIP2 p.Pro738Ser (c.2212C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CYFIP2 p.Pro738Ser (c.2212C>T)?

AlphaMissense predicts likely benign (score 0.1947) — an in-silico prediction, not a clinical call.

CYFIP2 p.Pro738Ser

c.2212C>T · rs1660734614 · VCV2007217

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1947 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1947	likely benign
REVEL	0.336	indeterminate
SaProt	LLR -7.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 32 kb · p 9.5e-12 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P763S vs ClinVar P738S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,020 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000547% 8/1,461,688 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,020
European (non-Finnish)	0.000593%	168,555

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: CYFIP2
Protein: p.Pro738Ser
Coding: c.2212C>T
MANE Select: NM_001037333
dbSNP: rs1660734614
Type: single nucleotide variant
Location: chr5:157330797 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.28

Full CYFIP2 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

Similar variants

CYFIP2 p.Pro738Arg Uncertain significance ★ ⚠ same residue
CYFIP2 p.Pro738Leu Uncertain significance ★ ⚠ same residue
CYFIP2 p.Pro738= Likely benign ★ same residue
CYFIP2 p.Glu640Lys Pathogenic ★★ same condition
CYFIP2 p.Ala1074Thr Uncertain significance ★★ ⚠ same condition
CYFIP2 p.Arg1041His Uncertain significance ★★ ⚠ same condition
CYFIP2 p.Arg1098His Uncertain significance ★★ ⚠ same condition
CYFIP2 p.Arg1098Leu 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/cyfip2-p-pro738ser (accessed [today's date]).

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