Is MAN2B2 p.Gln243Pro (c.728A>C) pathogenic?

MAN2B2 p.Gln243Pro (c.728A>C) is classified Benign/Likely benign in MAN2B2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.0487); Common (popmax 65.9%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about MAN2B2 p.Gln243Pro (c.728A>C)?

AlphaMissense predicts likely benign (score 0.0487) — an in-silico prediction, not a clinical call.

MAN2B2 p.Gln243Pro

Q: How common is MAN2B2 p.Gln243Pro (c.728A>C) in the general population?

MAN2B2 p.Gln243Pro (c.728A>C) is common (popmax 65.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.728A>C · rs2301796 · VCV2688006

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0487 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 65.9%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0487	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -3.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.003	GERP -2.5
Regional constraint	o/e 0.96	unconstrained · MANE · 46 kb · p 0.14 · regional, not allelic
Overall
CADD	1.511	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 65.9% East Asian · 29,522/44,808 alleles

Filtering AF 65.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 65%

Overall 46.6% 752,096/1,613,296 alleles · common exomes 690,283/1,461,158 · genomes 61,813/152,138 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	65.9%	2
South Asian	50.8%	2
Admixed American	47.7%	2
Ashkenazi Jewishnot grpmax-eligible	47.7%	2
European (non-Finnish)	47.4%	2
Remaining individualsnot grpmax-eligible	46.1%	2
Finnishnot grpmax-eligible	41.2%	2
Middle Eastern	38.2%	3
Amishnot grpmax-eligible	34.2%	3
African / African-American	22.6%	4

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: MAN2B2
Protein: p.Gln243Pro
Coding: c.728A>C
MANE Select: NM_015274
dbSNP: rs2301796
Type: single nucleotide variant
Location: chr4:6593220 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.55
Residue 243: a UniProt-annotated variant site (in)

Full MAN2B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAN2B2 p.Gln615Ter Pathogenic/Likely pathogenic ★★ same type
MAN2B2 p.Trp284Ter Pathogenic/Likely pathogenic ★★ same type
MAN2B2 p.Ala155Thr Uncertain significance ★★ ⚠ same type
MAN2B2 p.Ala868Thr Uncertain significance ★★ ⚠ same type
MAN2B2 p.Arg411His Uncertain significance ★★ ⚠ same type
MAN2B2 p.Arg447Gly Uncertain significance ★★ ⚠ same type
MAN2B2 p.Arg683Gln Uncertain significance ★★ ⚠ same type
MAN2B2 p.Arg975Ser 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/man2b2-p-gln243pro (accessed [today's date]).

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