Is REV3L p.Pro522Ser (c.1564C>T) pathogenic?

REV3L p.Pro522Ser (c.1564C>T) is classified Uncertain significance in REV3L (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-11). AlphaMissense: likely pathogenic (0.7251); Ultra-rare (popmax 0.0111%, eas); Associated with Inborn genetic diseases.

What condition is associated with REV3L p.Pro522Ser (c.1564C>T)?

REV3L p.Pro522Ser (c.1564C>T) is associated with Inborn genetic diseases (ClinVar).

How common is REV3L p.Pro522Ser (c.1564C>T) in the general population?

REV3L p.Pro522Ser (c.1564C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about REV3L p.Pro522Ser (c.1564C>T)?

AlphaMissense predicts likely pathogenic (score 0.7251) — an in-silico prediction, not a clinical call.

REV3L p.Pro522Ser

c.1564C>T · VCV3313795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7251 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7251	likely pathogenic
REVEL	0.235	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 57 kb · p 7.2e-05 · regional, not allelic
Overall
CADD	26.3	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 0.0111% East Asian · 5/44,848 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00031% 5/1,613,702 alleles · ultra-rare exomes 5/1,461,452 · genomes 0/152,250 · joint denominator

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: REV3L
Protein: p.Pro522Ser
Coding: c.1564C>T
MANE Select: NM_001372078
Type: single nucleotide variant
Location: chr6:111377734 (GRCh38)
Gene constraint: LOEUF 0.261 · pLI 1.00 (gnomAD)

Full REV3L 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

REV3L p.Arg1970Cys Uncertain significance ★★ ⚠ same condition
REV3L p.Ser518Asn Benign/Likely benign ★★ same condition
REV3L p.Ala1055Thr Uncertain significance ★ ⚠ same condition
REV3L p.Ala1094Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
REV3L p.Ala1147Thr Uncertain significance ★ ⚠ same condition
REV3L p.Ala1237Thr Uncertain significance ★ ⚠ same condition
REV3L p.Ala1252Glu Uncertain significance ★ ⚠ same condition
REV3L p.Ala1273Thr 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/rev3l-p-pro522ser (accessed [today's date]).

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