Is ADD1 p.Pro232Leu (c.695C>T) pathogenic?

ADD1 p.Pro232Leu (c.695C>T) is classified Uncertain significance in ADD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: likely benign (0.2865); Ultra-rare (popmax 0.0109%, nfe).

How common is ADD1 p.Pro232Leu (c.695C>T) in the general population?

ADD1 p.Pro232Leu (c.695C>T) is ultra-rare (popmax 0.0109%, nfe) (gnomAD).

What do computational predictors say about ADD1 p.Pro232Leu (c.695C>T)?

AlphaMissense predicts likely benign (score 0.2865) — an in-silico prediction, not a clinical call.

ADD1 p.Pro232Leu

c.695C>T · rs370683439 · VCV2293516

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2865 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2865	likely benign
REVEL	0.782	moderately pathogenic-leaning
SaProt	LLR -12.92	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 53 kb · p 0.026 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0109% European (non-Finnish) · 128/1,176,732 alleles

Filtering AF 0.0093% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00874%

Overall 0.00856% 137/1,601,376 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0109%	9,193
Remaining individualsnot grpmax-eligible	0.00806%	12,406
Finnishnot grpmax-eligible	0.00313%	31,943
South Asian	0.00228%	43,931

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: ADD1
Protein: p.Pro232Leu
Coding: c.695C>T
MANE Select: NM_001354761
dbSNP: rs370683439
Type: single nucleotide variant
Location: chr4:2894685 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.73

Full ADD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADD1 p.Val234= Benign ★★ same type
ADD1 p.Val559Met Benign ★★ same type
ADD1 c.2047+530G>A Uncertain significance ★ same type
ADD1 c.2047+541G>T Uncertain significance ★ same type
ADD1 p.Ala137Val Uncertain significance ★ ⚠ same type
ADD1 p.Ala151Thr Uncertain significance ★ ⚠ same type
ADD1 p.Ala156Thr Uncertain significance ★ ⚠ same type
ADD1 p.Ala18Thr Uncertain significance ★ same type

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/add1-p-pro232leu (accessed [today's date]).

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