Is RFX7 p.Pro656Ser (c.1966C>T) pathogenic?

RFX7 p.Pro656Ser (c.1966C>T) is classified Uncertain significance in RFX7 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.1505); Ultra-rare (popmax 0.0942%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RFX7 p.Pro656Ser (c.1966C>T)?

RFX7 p.Pro656Ser (c.1966C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RFX7 p.Pro656Ser (c.1966C>T) in the general population?

RFX7 p.Pro656Ser (c.1966C>T) is ultra-rare (popmax 0.0942%, nfe) (gnomAD).

What do computational predictors say about RFX7 p.Pro656Ser (c.1966C>T)?

AlphaMissense predicts likely benign (score 0.1505) — an in-silico prediction, not a clinical call.

RFX7 p.Pro656Ser

c.1966C>T · rs201488404 · VCV2336579

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1505 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0942%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1505	likely benign
REVEL	0.072	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 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,605 bp · p 0.78 · regional, not allelic
Overall
CADD	23.5	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 is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P559S vs ClinVar P656S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0942% European (non-Finnish) · 1,111/1,179,874 alleles

Filtering AF 0.0895% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0877%

Overall 0.0719% 1,161/1,613,666 alleles · ultra-rare exomes 1,079/1,461,570 · genomes 82/152,096 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0942%	1,062
Remaining individualsnot grpmax-eligible	0.032%	3,123
Middle Eastern	0.0164%	6,084
African / African-American	0.0147%	6,805
Admixed American	0.0117%	8,570
South Asian	0.00769%	13,011
Finnishnot grpmax-eligible	0.00469%	21,300
East Asian	0.00223%	44,898

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: RFX7
Protein: p.Pro656Ser
Coding: c.1966C>T
MANE Select: NM_022841
dbSNP: rs201488404
Type: single nucleotide variant
Location: chr15:56095762 (GRCh38)
Gene constraint: LOEUF 0.3 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 43.61 · 2 PDB

Full RFX7 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

RFX7 p.Pro700Ser Uncertain significance ★★ ⚠ same condition
RFX7 p.Ser100Cys Uncertain significance ★★ same condition
RFX7 p.Ser1070Thr Uncertain significance ★★ ⚠ same condition
RFX7 p.Ser974Asn Uncertain significance ★★ ⚠ same condition
RFX7 p.Val1127Leu Uncertain significance ★★ same condition
RFX7 p.Ala425Thr Likely benign ★★ same condition
RFX7 p.Ile1384Thr Likely benign ★★ same condition
RFX7 p.Met1033Thr Likely benign ★★ 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/rfx7-p-pro656ser (accessed [today's date]).

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