Is REV3L p.Ala1237Thr (c.3709G>A) pathogenic?

REV3L p.Ala1237Thr (c.3709G>A) is classified Uncertain significance in REV3L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-21). AlphaMissense: likely benign (0.0696); Very rare (popmax 0.00153%, nfe); Associated with Inborn genetic diseases.

What condition is associated with REV3L p.Ala1237Thr (c.3709G>A)?

REV3L p.Ala1237Thr (c.3709G>A) is associated with Inborn genetic diseases (ClinVar).

How common is REV3L p.Ala1237Thr (c.3709G>A) in the general population?

REV3L p.Ala1237Thr (c.3709G>A) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about REV3L p.Ala1237Thr (c.3709G>A)?

AlphaMissense predicts likely benign (score 0.0696) — an in-silico prediction, not a clinical call.

REV3L p.Ala1237Thr

c.3709G>A · VCV3788396

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0696 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0696	likely benign
REVEL	0.141	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 -0.21	GERP -2.7
Regional constraint	o/e 0.92	unconstrained · MANE · 57 kb · p 7.2e-05 · regional, not allelic
Overall
CADD	10.25	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,179,818 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00428% 69/1,613,492 alleles · very rare exomes 61/1,461,320 · genomes 8/152,172 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.149%	672
Remaining individualsnot grpmax-eligible	0.0112%	8,923
European (non-Finnish)grpmax	0.00153%	65,545

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala1237Thr
Coding: c.3709G>A
MANE Select: NM_001372078
Type: single nucleotide variant
Location: chr6:111374646 (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.Ala1252Glu Uncertain significance ★ ⚠ same condition
REV3L p.Ala1273Thr Uncertain significance ★ ⚠ same condition
REV3L p.Ala1820Val 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-ala1237thr (accessed [today's date]).

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