Is MAN2B2 p.Ser174Phe (c.521C>T) pathogenic?

MAN2B2 p.Ser174Phe (c.521C>T) is classified Uncertain significance in MAN2B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-29). AlphaMissense: likely pathogenic (0.8157); Ultra-rare (popmax 0.0666%, afr).

How common is MAN2B2 p.Ser174Phe (c.521C>T) in the general population?

MAN2B2 p.Ser174Phe (c.521C>T) is ultra-rare (popmax 0.0666%, afr) (gnomAD).

What do computational predictors say about MAN2B2 p.Ser174Phe (c.521C>T)?

AlphaMissense predicts likely pathogenic (score 0.8157) — an in-silico prediction, not a clinical call.

MAN2B2 p.Ser174Phe

c.521C>T · rs140227562 · VCV3122544

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8157 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0666%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8157	likely pathogenic
REVEL	0.276	benign-leaning
SaProt	LLR -9.45	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 1.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 46 kb · p 0.14 · regional, not allelic
Overall
CADD	25.0	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 0.0666% African / African-American · 50/75,062 alleles

Filtering AF 0.0519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0466%

Overall 0.00359% 58/1,613,844 alleles · ultra-rare exomes 33/1,461,478 · genomes 25/152,366 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0666%	1,501
Remaining individualsnot grpmax-eligible	0.0096%	10,416
South Asian	0.0011%	91,070
European (non-Finnish)	8.47e-05%	1,180,004

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.Ser174Phe
Coding: c.521C>T
MANE Select: NM_015274
dbSNP: rs140227562
Type: single nucleotide variant
Location: chr4:6587125 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.55

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-ser174phe (accessed [today's date]).

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